Discovery of GLPG2737, a Potent Type 2 Corrector of CFTR for the Treatment of Cystic Fibrosis in Combination with a Potentiator and a Type 1 Co-correctorClick to copy article linkArticle link copied!
- Mathieu PizzoneroMathieu PizzoneroGalapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, FranceMore by Mathieu Pizzonero
- Rhalid AkkariRhalid AkkariGalapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, FranceMore by Rhalid Akkari
- Xavier Bock
- Romain Gosmini*Romain Gosmini*Email: [email protected]Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, FranceMore by Romain Gosmini
- Elsa De LemosElsa De LemosGalapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, FranceMore by Elsa De Lemos
- Béranger DuthionBéranger DuthionGalapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, FranceMore by Béranger Duthion
- Gregory NewsomeGregory NewsomeGalapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, FranceMore by Gregory Newsome
- Thi-Thu-Trang MaiThi-Thu-Trang MaiGalapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, FranceMore by Thi-Thu-Trang Mai
- Virginie RoquesVirginie RoquesGalapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, FranceMore by Virginie Roques
- Hélène Jary
- Jean-Michel LefrancoisJean-Michel LefrancoisGalapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, FranceMore by Jean-Michel Lefrancois
- Laetitia CherelLaetitia CherelGalapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, FranceMore by Laetitia Cherel
- Vanessa QuenehenVanessa QuenehenGalapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, FranceMore by Vanessa Quenehen
- Marielle BabelMarielle BabelGalapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, FranceMore by Marielle Babel
- Nuria MerayoNuria MerayoGalapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, FranceMore by Nuria Merayo
- Natacha BienvenuNatacha BienvenuGalapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, FranceMore by Natacha Bienvenu
- Oscar MammolitiOscar MammolitiGalapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, BelgiumMore by Oscar Mammoliti
- Ghjuvanni CotiGhjuvanni CotiGalapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, BelgiumMore by Ghjuvanni Coti
- Adeline PalisseAdeline PalisseGalapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, BelgiumMore by Adeline Palisse
- Marlon CowartMarlon CowartAbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064-1802, United StatesMore by Marlon Cowart
- Anurupa ShresthaAnurupa ShresthaAbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064-1802, United StatesMore by Anurupa Shrestha
- Stephen GreszlerStephen GreszlerAbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064-1802, United StatesMore by Stephen Greszler
- Steven Van Der PlasSteven Van Der PlasGalapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, BelgiumMore by Steven Van Der Plas
- Koen Jansen
- Pieter Claes
- Mia Jans
- Maarten Gees
- Monica BorgonoviMonica BorgonoviGalapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, FranceMore by Monica Borgonovi
- Gert De WildeGert De WildeGalapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, BelgiumMore by Gert De Wilde
- Katja ConrathKatja ConrathGalapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, BelgiumMore by Katja Conrath
Abstract
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) protein. This epithelial anion channel regulates the active transport of chloride and bicarbonate ions across membranes. Mutations result in reduced surface expression of CFTR channels with impaired functionality. Correctors are small molecules that support the trafficking of CFTR to increase its membrane expression. Such correctors can have different mechanisms of action. Combinations may result in a further improved therapeutic benefit. We describe the identification and optimization of a new pyrazolol3,4-bl pyridine-6-carboxylic acid series with high potency and efficacy in rescuing CFTR from the cell surface. Investigations showed that carboxylic acid group replacement with acylsulfonamides and acylsulfonylureas improved ADMET and PK properties, leading to the discovery of the structurally novel co-corrector GLPG2737. The addition of GLPG2737 to the combination of the potentiator GLPG1837 and C1 corrector 4 led to an 8-fold increase in the F508del CFTR activity.
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License Summary*
You are free to share(copy and redistribute) this article in any medium or format and to adapt(remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
*Disclaimer
This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials.
License Summary*
You are free to share(copy and redistribute) this article in any medium or format and to adapt(remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
*Disclaimer
This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials.
Introduction
Results and Discussion
GLPG2737 Profile
Figure 1
Figure 1. Structures of existing potentiators (1 and 3) and correctors (2, 4, and 5).
Hit Identification

Assay conditions are described in the Experimental Section using lumacaftor or 5 (3 μM) as the positive control. All values are the geometric mean calculated from at least two runs.
Calculated from measured fumic (unbound fraction in microsomes).
CLint, intrinsic clearance; CSE-HRP, cell surface expression-horse radish peroxidase; mic, microsome; hep, hepatocyte.
SAR Optimization

Assay conditions are described in the Experimental Section using Lumacaftor or 5 (3 μM) as the positive control. All values are the geometric mean calculated from at least two runs, except when mentioned.
Only one measure was done.
CSE-HRP, cell surface expression-horse radish peroxidase.

Assay conditions are described in the Experimental Section using lumacaftor or 5 (3 μM) as the positive control. All values are the geometric mean calculated from at least two runs, except when mentioned.
Only one measure was done.
CSE-HRP, cell surface expression-horse radish peroxidase.

Assay conditions are described in the Experimental Section using lumacaftor or 5 (3 μM) as the positive control. All values are the geometric mean calculated from at least two runs.
CSE-HRP, cell surface expression-horse radish peroxidase.

Assay conditions are described in the Experimental Section using lumacaftor or 5 (3 μM) as the positive control. All values are the geometric mean calculated from at least two runs, except when mentioned.
Only one measure was done.
CSE-HRP, cell surface expression-horse radish peroxidase.

Assay conditions are described in the Experimental Section using lumacaftor or 5 (3 μM) as the positive control. All values are the geometric mean calculated from at least two runs.
CSE-HRP, cell surface expression-horse radish peroxidase.
Figure 2
Figure 2. Plot of CSE HRP potency (X-axis, EC50 [nM]) and CSE HRP efficacy (Y-axis, % max activation) for acid (red), acylsulfonylurea (blue), and acylsulfonamide (yellow) analogues.
Pharmacokinetic Analysis
CL | Vss | PPB% (rat/human) | F (%) | |
---|---|---|---|---|
18 | 0.2 | 0.474 | 100/99 | − |
45 | 0.0246 | 0.195 | 99.97/99.65 | 63.4 |
Dose 1 mg/kg iv. CL: clearance (L/h/kg). Vss (L/kg). Dose 5 mg/kg po.

Assay conditions are described in the Experimental Section using 5 (3 μM) as the positive control. All values are the geometric mean calculated from at least two runs, except when mentioned.
In contrast to the other TECC experiments, after the 24 h incubation with a range of different concentrations, a fixed 1 μM C2 corrector concentration was added during the electrophysiological recording.
Data generated by AbbVie team.
Data generated by Galapagos.
CSE-HRP, cell surface expression-horse radish peroxidase; HBE, human bronchial epithelial; TECC, transepithelial clamp circuit.
XlogP3 | TPSA | acidic pKaa | most basic pKaa | |
---|---|---|---|---|
45 | 4.02 | 142 | 4.82 | 3.93 |
46 | 3.76 | 106 | 5.16 | 3.13 |
47 | 3.32 | 115 | 5.13 | 3.21 |
48 | 3.13 | 129 | 5.00 | 2.94 |
49 | 3.13 | 118 | 5.1 | 7.04 |
50 | 3.23 | 118 | 4.9 | 7.01 |
51 | 3.14 | 121 | 4.57 | 6.96 |
52 | 3.92 | 121 | 4.78 | 7.96 |
Calculated with Simul Plus.
CLp (L/h/kg) rat/dog | CLu (L/h/kg) rat/dog | t1/2 iv (h) rat/dog | Vss (L/kg) rat/dog | PPB (%) rat/dog/human | |
---|---|---|---|---|---|
51 | 0.19/0.16 | 13.2/12.1 | 3.6/4.9 | 0.81/0.9 | 98.5/99.0/98.7 |
52 | 0.32/0.21 | 20.0/10.7 | 3.45/5.4 | 1.38/1.37 | 98.4/97.5/98.0 |
CLp, plasma clearance; CLu, unbound clearance; t1/2 iv, half-life following iv dosing; Vss, volume of distribution at steady state; PPB, plasma protein binding.
C2 corrector | pEC50 | EC50 (nM) | fold |
---|---|---|---|
– | 7.9 ± 0.18 (n = 6) | 13 | 1 |
45 | 6.8 (n = 1) | 154 | 11.8 |
49 | 6.9 ± 0.10 (n = 5) | 119 | 9.2 |
51 | 7.2 ± 0.09 (n = 3) | 62a | 4.8 |
52 (GLPG2737) | 7.2 ± 0.08 (n = 5) | 71a | 5.5 |
The differences in the reported values are due to the rounding of data on the logarithmic scale.
Figure 3
Figure 3. TECC current measurement assay in primary CF derived HBE cells (current induced after FSK stimulation after 24 h of incubation with correctors and potentiators). (A) Dose response of GLPG2737 in combination with 1 μM potentiator GLPG1837 and 0.15 μM corrector 4. (B) Comparison of a dose response for GLPG1837 in combination with 1 μM compound 52 + 0.15 μM C1 corrector 4 or only corrector 4.
MDCK-MDR1: PA2B (cm × 10–6 s–1)/ER | 5.45/4.35 (n = 2) |
Caco-2: PA2B (cm × 10–6 s–1)/ER | 24.5/1.27 (n = 1) |
thermodynamic solubility | |
FASSGF | 10.9 μg/mL |
pH 7.4 | 9.9 μg/mL |
measured pKa: potentiometric method/UV methodb | |
acylsulfonamyl pKa | 4.96/4.74 |
piperidine pKa | 8.42/8.51 |
CYP inhibition in HLM | IC50 (μM) |
CYPlA2 phenacetin | >100 |
CYP2C19 S-mephenytoin | >33 |
CYP2C9 diclofenac | 1.4 |
CYP2D6 dextromethorphan | >100 |
CYP3A4 midazolam | >100 |
CYP3A4 testosterone | >100 |
MDCK-MDR1, permeability assay using Madin-Darby canine kidney cells transfected with MDR1; PA2B, apparent permeability from A side to B side; ER, efflux ratio; Caco-2, permeability assay in human epithelial cell line (colorectal adenocarcinoma cells); FASSGF, fasted stimulated gastric fluid; CYP, cytochrome P450; HLM, human liver microsomes.
pKa values were measured at Charles River.
Chemical Synthesis
Scheme 1
Scheme 1. a
aa) 130–170 °C. 3–40 h, (54a: 67%, 54b: 95%); b) Phenyl dichlorophosphate. 170 °C. 15–21 h, (55a: 75%, 55b: 85%); c) CO(g). Pd(dppf)Cl2.DCM. sodium acetate. 1,4-dioxane. MeOH. 40–60 °C. 2–40 h, (56a: 58%, 56b: 63%); d) Amine. DIPEA or NEt3. MeCN or DMSO. 50–130 °C, (46–94%); e) NaOH or LiOH. H2O. MeOH and/or THF or dioxane. rt to 70 °C, (79–100%); f) EDC.HCl. corresponding nucleophile DMAP. DCM or THF or MeCN. rt. 20 h (30–80%) or CDI. DMF corresponding nucleophile. DBU. Rt (49: 100%, 52: 67%).
Conclusion
Experimental Section
General Chemistry Methods
Illustrative Synthesis of GLPG2737: 3-Cyclobutyl-N-(N,N-dimethylsulfamoyl)-1-(4-fluorophenyl)-4-(4-methoxy-[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide (52)
Step a: 3-Cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-4,6-diol (54b)
Step b: 4,6-Dichloro-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine (55b)
Step c: Methyl 4-Chloro-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (56b)
Step d: Methyl 3-Cyclobutyl-1-(4-fluorophenyl)-4-(4-methoxy-[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (57f)
Step e: 3-Cyclobutyl-1-(4-fluorophenyl)-4-(4-methoxy-[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (58g)
Step f: 3-Cyclobutyl-N-(N,N-dimethylsulfamoyl)-1-(4-fluorophenyl)-4-(4-methoxy-[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide (52) or GLPG2737
Cell Culture
Cell Surface Expression Horseradish Peroxidase Assay (CSE-HRP Assay)
Transepithelial Clamp Circuit (TECC)
Liver Microsomal Stability (LMS) Assay
Fu, mic (Fraction Unbound in Microsomes)
Hepatocyte Stability Assay
Plasma Protein Binding
PK Rat
CYP3A4 Induction
MDCK-MDR1 Assay
Intestinal Permeability on Caco-2 Cells
Thermodynamic Solubility
CYP Reversible Inhibition Assay
PK Dog
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c01790.
Supplemental PK tables; general methods for compound synthesis/analysis, general methods for synthesis of intermediates, and experimental procedure for the synthesis of intermediates and compounds 8–52; HPLC traces of compounds 8–52 (PDF)
Formula strings (CSV)
Terms & Conditions
Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.
Acknowledgments
The authors thank the AbbVie team and Line Oste for their contributions to the studies presented in this article. Publication coordination was provided by John Gonzalez, PhD, a consultant funded by Galapagos NV. Editorial and publications management support was provided by PharmaGenesis London, London, UK, funded by Galapagos NV.
BID | bis in die or twice a day |
CDI | carbonyldiimidazole |
CF | cystic fibrosis |
CFTR | cystic fibrosis transmembrane conductance regulator |
CL | clearance |
CLu | unbound clearance |
Clint | intrinsic clearance |
CLogP | calculated log partition coefficient (octanol/water) |
CO | carbon monoxide |
CSE | cell surface expression |
CYP | cytochrome P450 |
DIPEA | diisopropylethylamine |
EDC | 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide |
F | oral bioavailability |
Fa | the fraction of the administered dose that is absorbed into the systemic circulation |
Fg | the fraction of the absorbed dose that escapes first-pass metabolism in the liver and reaches the systemic circulation unchanged |
FASSGF | Fasted State Simulated Gastric Fluid |
FSK | forskolin |
HEPES | buffer made from 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid |
HBE | human bronchial epithelial |
HEP | hepatocyte |
HLM | human liver microsomes |
HRP | horse radish peroxidase |
LMS | liver microsomes stability |
MC | methyl cellulose |
MDCK | Madin-Darby canine kidney |
MeCN | acetonitrile |
NADP | nicotinamide adenine dinucleotide phosphate |
PD | pharmacodynamics |
PEG | polyethylene glycol |
PO | per os (oral dosing) |
pKa | acid dissociation constant |
QD | quaque die once a day |
TECC | transepithelial clamp circuit |
T1/2 | eff, effective half-life (MRT*Vd,ss/CL) |
tPSA | total polar surface area |
Vd,ss | volume of distribution at steady state |
WT | wild type |
References
This article references 25 other publications.
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- 7Hadida, S.; Van Goor, F.; Zhou, J.; Arumugam, V.; McCartney, J.; Hazlewood, A.; Decker, C.; Negulescu, P.; Grootenhuis, P. D. Discovery of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, ivacaftor), a potent and orally bioavailable CFTR potentiator. J. Med. Chem. 2014, 57 (23), 9776– 9795, DOI: 10.1021/jm5012808Google ScholarThere is no corresponding record for this reference.
- 8Ren, H. Y.; Grove, D. E.; De La Rosa, O.; Houck, S. A.; Sopha, P.; Van Goor, F.; Hoffman, B. J.; Cyr, D. M. VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol. Biol. Cell 2013, 24 (19), 3016– 3024, DOI: 10.1091/mbc.e13-05-0240Google ScholarThere is no corresponding record for this reference.
- 9Heijerman, H. G. M.; McKone, E. F.; Downey, D. G.; Van Braeckel, E.; Rowe, S. M.; Tullis, E.; Mall, M. A.; Welter, J. J.; Ramsey, B. W.; McKee, C. M.; Marigowda, G.; Moskowitz, S. M.; Waltz, D.; Sosnay, P. R.; Simard, C.; Ahluwalia, N.; Xuan, F.; Zhang, Y.; Taylor-Cousar, J. L.; McCoy, K. S. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet 2019, 394 (10212), 1940– 1948, DOI: 10.1016/S0140-6736(19)32597-8Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitV2msr%252FF&md5=6e00357faca65805cf40d67eec84dc3fEfficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trialHeijerman, Harry G. M.; McKone, Edward F.; Downey, Damian G.; Van Braeckel, Eva; Rowe, Steven M.; Tullis, Elizabeth; Mall, Marcus A.; Welter, John J.; Ramsey, Bonnie W.; McKee, Charlotte M.; Marigowda, Gautham; Moskowitz, Samuel M.; Waltz, David; Sosnay, Patrick R.; Simard, Christopher; Ahluwalia, Neil; Xuan, Fengjuan; Zhang, Yaohua; Taylor-Cousar, Jennifer L.; McCoy, Karen S.Lancet (2019), 394 (10212), 1940-1948CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addn. of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clin. outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation. This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory vol. in 1 s (ppFEV1) of 40-90%, inclusive. After a 4-wk tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 wk of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h vs. tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the abs. change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were abs. change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548. Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-wk treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concn. (LSM treatment difference -45·1 mmol/L [95% CI -50·1 to -40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor. Elexacaftor plus tezacaftor plus ivacaftor provided clin. robust benefit compared with tezacaftor plus ivacaftor alone, with a favorable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation.Vertex Pharmaceuticals.
- 10de Wilde, G.; Gees, M.; Musch, S.; Verdonck, K.; Jans, M.; Wesse, A. S.; Singh, A. K.; Hwang, T. C.; Christophe, T.; Pizzonero, M.; Van der Plas, S.; Desroy, N.; Cowart, M.; Stouten, P.; Nelles, L.; Conrath, K. Identification of GLPG/ABBV-2737, a Novel Class of Corrector, Which Exerts Functional Synergy With Other CFTR Modulators. Front. Pharmacol. 2019, 10, 514, DOI: 10.3389/fphar.2019.00514Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVGkt77P&md5=9f4a5c0ab242a599af1bb45c73a88c35Identification of GLPG/ABBV-2737, a novel class of corrector, which exerts functional synergy with other CFTR modulatorsde Wilde, Gert; Gees, Maarten; Musch, Sara; Verdonck, Katleen; Jans, Mia; Wesse, Anne-Sophie; Singh, Ashvani K.; Hwang, Tzyh-Chang; Christophe, Thierry; Pizzonero, Mathieu; Van der Plas, Steven; Desroy, Nicolas; Cowart, Marlon; Stouten, Pieter; Nelles, Luc; Conrath, KatjaFrontiers in Pharmacology (2019), 10 (), 514CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)The deletion of phenylalanine at position 508 (F508del) in cystic fibrosis transmembrane conductance regulator (CFTR) causes a severe defect in folding and trafficking of the chloride channel resulting in its absence at the plasma membrane of epithelial cells leading to cystic fibrosis. Progress in the understanding of the disease increased over the past decades and led to the awareness that combinations of mechanistically different CFTR modulators are required to obtain meaningful clin. benefit. Today, there remains an unmet need for identification and development of more effective CFTR modulator combinations to improve existing therapies for patients carrying the F508del mutation. Here, we describe the identification of a novel F508del corrector using functional assays. We provide exptl. evidence that the clin. candidate GLPG/ABBV-2737 represents a novel class of corrector exerting activity both on its own and in combination with VX809 or GLPG/ABBV-2222.
- 11Davies, J. C.; Van de Steen, O.; van Koningsbruggen-Rietschel, S.; Drevinek, P.; Derichs, N.; McKone, E. F.; Kanters, D.; Allamassey, L.; Namour, F.; de Kock, H.; Conrath, K. GLPG1837, a CFTR potentiator, in p.Gly551Asp (G551D)-CF patients: An open-label, single-arm, phase 2a study (SAPHIRA1). J. Cyst. Fibros. 2019, 18 (5), 693– 699, DOI: 10.1016/j.jcf.2019.05.006Google ScholarThere is no corresponding record for this reference.
- 12Bell, S. C.; Barry, P. J.; De Boeck, K.; Drevinek, P.; Elborn, J. S.; Plant, B. J.; Minic, P.; Van Braeckel, E.; Verhulst, S.; Muller, K.; Kanters, D.; Bellaire, S.; de Kock, H.; Geller, D. E.; Conrath, K.; Van de Steen, O.; van der Ent, K. CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials. J. Cyst. Fibros. 2019, 18 (5), 700– 707, DOI: 10.1016/j.jcf.2019.04.014Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M7isFGntg%253D%253D&md5=68c6243b1f7438e9a61a3bca48618ddcCFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trialsBell Scott C; Barry Peter J; De Boeck Kris; Drevinek Pavel; Elborn J Stuart; Plant Barry J; Minic Predag; Van Braeckel Eva; Verhulst Stijn; Muller Karine; Kanters Desiree; de Kock Herman; Conrath Katja; Van de Steen Olivier; Bellaire Susan; Geller David E; van der Ent KorsJournal of cystic fibrosis : official journal of the European Cystic Fibrosis Society (2019), 18 (5), 700-707 ISSN:.BACKGROUND: Several treatment approaches in cystic fibrosis (CF) aim to correct CF transmembrane conductance regulator (CFTR) function; the efficacy of each approach is dependent on the mutation(s) present. A need remains for more effective treatments to correct functional deficits caused by the F508del mutation. METHODS: Two placebo-controlled, phase 2a studies evaluated GLPG2222, given orally once daily for 29 days, in subjects homozygous for F508del (FLAMINGO) or heterozygous for F508del and a gating mutation, receiving ivacaftor (ALBATROSS). The primary objective of both studies was to assess safety and tolerability. Secondary objectives included assessment of pharmacokinetics, and of the effect of GLPG2222 on sweat chloride concentrations, pulmonary function and respiratory symptoms. RESULTS: Fifty-nine and 37 subjects were enrolled into FLAMINGO and ALBATROSS, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.2% (14/48) of subjects in FLAMINGO and 40.0% (12/30) in ALBATROSS; most were mild to moderate in severity and comprised primarily respiratory, gastrointestinal, and infection events. There were no deaths or discontinuations due to TEAEs. Dose-dependent decreases in sweat chloride concentrations were seen in GLPG2222-treated subjects (maximum decrease in FLAMINGO: -17.6 mmol/L [GLPG2222 200 mg], p < 0.0001; ALBATROSS: -7.4 mmol/L [GLPG2222 300 mg], p < 0.05). No significant effects on pulmonary function or respiratory symptoms were reported. Plasma GLPG2222 concentrations in CF subjects were consistent with previous studies in healthy volunteers and CF subjects. CONCLUSIONS: GLPG2222 was well tolerated. Sweat chloride reductions support on-target enhancement of CFTR activity in subjects with F508del mutation(s). Significant improvements in clinical endpoints were not demonstrated. Observed safety results support further evaluation of GLPG2222, including in combination with other CFTR modulators. FUNDING: Galapagos NV. Clinical trial registration numbers FLAMINGO, NCT03119649; ALBATROSS, NCT03045523.
- 13Singh, A. K.; Fan, Y.; Balut, C.; Alani, S.; Manelli, A. M.; Swensen, A. M.; Jia, Y.; Neelands, T. R.; Vortherms, T. A.; Liu, B.; Searle, X. B.; Wang, X.; Gao, W.; Hwang, T. C.; Ren, H. Y.; Cyr, D.; Kym, P. R.; Conrath, K.; Tse, C. Biological Characterization of F508delCFTR Protein Processing by the CFTR Corrector ABBV-2222/GLPG2222. J. Pharmacol. Exp. Ther. 2020, 372 (1), 107– 118, DOI: 10.1124/jpet.119.261800Google ScholarThere is no corresponding record for this reference.
- 14Bredael, K.; Geurs, S.; Clarisse, D.; De Bosscher, K.; D’hooghe, M. Carboxylic Acid Bioisosteres in Medicinal Chemistry: Synthesis and Properties. J. Chem. 2022, 2022, 2164558, DOI: 10.1155/2022/2164558Google ScholarThere is no corresponding record for this reference.
- 15Smith, D. A.; Beaumont, K.; Maurer, T. S.; Di, L. Volume of Distribution in Drug Design. J. Med. Chem. 2015, 58 (15), 5691– 5698, DOI: 10.1021/acs.jmedchem.5b00201Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXltFSlsb0%253D&md5=2c7289b3602a8edef2d9ef0e6a82e483Volume of Distribution in Drug DesignSmith, Dennis A.; Beaumont, Kevin; Maurer, Tristan S.; Di, LiJournal of Medicinal Chemistry (2015), 58 (15), 5691-5698CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Vol. of distribution is one of the most important pharmacokinetic properties of a drug candidate. It is a major determinant of half-life and dosing frequency of a drug. For a similar log P, a basic mol. will tend to exhibit higher vol. of distribution than a neutral mol. Acids often exhibit low vols. of distribution. Although a design strategy against vol. of distribution can be advantageous in achieving desirable dosing regimen, it must be well-directed in order to avoid detrimental effects to other important properties. Strategies to increase vol. of distribution include adding lipophilicity and introducing basic functional groups in a way that does not increase metabolic clearance.
- 16Di, L.; Breen, C.; Chambers, R.; Eckley, S. T.; Fricke, R.; Ghosh, A.; Harradine, P.; Kalvass, J. C.; Ho, S.; Lee, C. A.; Marathe, P.; Perkins, E. J.; Qian, M.; Tse, S.; Yan, Z.; Zamek-Gliszczynski, M. J. Industry Perspective on Contemporary Protein-Binding Methodologies: Considerations for Regulatory Drug-Drug Interaction and Related Guidelines on Highly Bound Drugs. J. Pharm. Sci. 2017, 106 (12), 3442– 3452, DOI: 10.1016/j.xphs.2017.09.005Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1Gmu7nO&md5=316d6854cc04968107b609a9ccae6eedIndustry Perspective on Contemporary Protein-Binding Methodologies: Considerations for Regulatory Drug-Drug Interaction and Related Guidelines on Highly Bound DrugsDi, Li; Breen, Christopher; Chambers, Rob; Eckley, Sean T.; Fricke, Robert; Ghosh, Avijit; Harradine, Paul; Kalvass, J. Cory; Ho, Stacy; Lee, Caroline A.; Marathe, Punit; Perkins, Everett J.; Qian, Mark; Tse, Susanna; Yan, Zhengyin; Zamek-Gliszczynski, Maciej J.Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2017), 106 (12), 3442-3452CODEN: JPMSAE; ISSN:0022-3549. (Elsevier Inc.)A review. Regulatory agencies have recently issued drug-drug interaction guidelines, which require detn. of plasma protein binding (PPB). To err on the conservative side, the agencies recommend that a 0.01 lower limit of fraction unbound (fu) be used for highly bound compds. (>99%), irresp. of the actual measured values. While this may avoid false negatives, the recommendation would likely result in a high rate of false pos. predictions, resulting in unnecessary clin. studies and more stringent inclusion/exclusion criteria, which may add cost and time in delivery of new medicines to patients. In this perspective, the authors provide a review of current approaches to measure PPB, and important determinants in enabling the accuracy and precision in these measurements. The ability to measure fu is further illustrated by a cross-company data comparison of PPB for warfarin and itraconazole, demonstrating good concordance of the measured fu values. The data indicate that fu values of ≤0.01 may be detd. accurately across labs. when appropriate methods are used. These data, along with numerous other examples presented in the literature, support the use of exptl. measured fu values for drug-drug interaction predictions, rather than using the arbitrary cutoff value of 0.01 as recommended in current regulatory guidelines.
- 17Davies, M.; Jones, R. D. O.; Grime, K.; Jansson-Lofmark, R.; Fretland, A. J.; Winiwarter, S.; Morgan, P.; McGinnity, D. F. Improving the Accuracy of Predicted Human Pharmacokinetics: Lessons Learned from the AstraZeneca Drug Pipeline Over Two Decades. Trends Pharmacol. Sci. 2020, 41 (6), 390– 408, DOI: 10.1016/j.tips.2020.03.004Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXntlSisb0%253D&md5=59e5d969ba3de23dc522ab5d2ab14801Improving the Accuracy of Predicted Human Pharmacokinetics: Lessons Learned from the AstraZeneca Drug Pipeline Over Two DecadesDavies, Michael; Jones, Rhys D. O.; Grime, Ken; Jansson-Lofmark, Rasmus; Fretland, Adrian J.; Winiwarter, Susanne; Morgan, Paul; McGinnity, Dermot F.Trends in Pharmacological Sciences (2020), 41 (6), 390-408CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)During drug discovery and prior to the first human dose of a novel candidate drug, the pharmacokinetic (PK) behavior of the drug in humans is predicted from preclin. data. This helps to inform the likelihood of achieving therapeutic exposures in early clin. development. Once clin. data are available, the obsd. human PK are compared with predictions, providing an opportunity to assess and refine prediction methods. Application of best practice in exptl. data generation and predictive methodologies, and a focus on robust mechanistic understanding of the candidate drug disposition properties before nomination to clin. development, have led to maximizing the probability of successful PK predictions so that 83% of AstraZeneca drug development projects progress in the clinic with no PK issues; and 71% of key PK parameter predictions [64% of area under the curve (AUC) predictions; 78% of max. concn. (Cmax) predictions; and 70% of half-life predictions] are accurate to within twofold. Here, we discuss methods to predict human PK used by AstraZeneca, how these predictions are assessed and what can be learned from evaluating the predictions for 116 candidate drugs.
- 18Lassalas, P.; Gay, B.; Lasfargeas, C.; James, M. J.; Tran, V.; Vijayendran, K. G.; Brunden, K. R.; Kozlowski, M. C.; Thomas, C. J.; Smith, A. B.; Huryn, D. M.; Ballatore, C. Structure Property Relationships of Carboxylic Acid Isosteres. J. Med. Chem. 2016, 59 (7), 3183– 3203, DOI: 10.1021/acs.jmedchem.5b01963Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktFartbY%253D&md5=34490fc72fdb321d8c9751bef1bf79c5Structure Property Relationships of Carboxylic Acid IsosteresLassalas, Pierrik; Gay, Bryant; Lasfargeas, Caroline; James, Michael J.; Tran, Van; Vijayendran, Krishna G.; Brunden, Kurt R.; Kozlowski, Marisa C.; Thomas, Craig J.; Smith, Amos B.; Huryn, Donna M.; Ballatore, CarloJournal of Medicinal Chemistry (2016), 59 (7), 3183-3203CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The replacement of a carboxylic acid with a surrogate structure, or (bio)-isostere, is a classical strategy in medicinal chem. The general underlying principle is that by maintaining the features of the carboxylic acid crit. for biol. activity, but appropriately modifying the physicochem. properties, improved analogs may result. In this context, a systematic assessment of the physicochem. properties of carboxylic acid isosteres would be desirable to enable more informed decisions of potential replacements to be used for analog design. Herein we report the structure-property relationships (SPR) of 35 phenylpropionic acid derivs., in which the carboxylic acid moiety is replaced with a series of known isosteres. The data set generated provides an assessment of the relative impact on the physicochem. properties that these replacements may have compared to the carboxylic acid analog. As such, this study presents a framework for how to rationally apply isosteric replacements of the carboxylic acid functional group.
- 19Gentles, R. G.; Ding, M.; Bender, J. A.; Bergstrom, C. P.; Grant-Young, K.; Hewawasam, P.; Hudyma, T.; Martin, S.; Nickel, A.; Regueiro-Ren, A.; Tu, Y.; Yang, Z.; Yeung, K. S.; Zheng, X.; Chao, S.; Sun, J. H.; Beno, B. R.; Camac, D. M.; Chang, C. H.; Gao, M.; Morin, P. E.; Sheriff, S.; Tredup, J.; Wan, J.; Witmer, M. R.; Xie, D.; Hanumegowda, U.; Knipe, J.; Mosure, K.; Santone, K. S.; Parker, D. D.; Zhuo, X.; Lemm, J.; Liu, M.; Pelosi, L.; Rigat, K.; Voss, S.; Wang, Y.; Wang, Y. K.; Colonno, R. J.; Gao, M.; Roberts, S. B.; Gao, Q.; Ng, A.; Meanwell, N. A.; Kadow, J. F. Discovery and preclinical characterization of the cyclopropylindolobenzazepine BMS-791325, a potent allosteric inhibitor of the hepatitis C virus NS5B polymerase. J. Med. Chem. 2014, 57 (5), 1855– 1879, DOI: 10.1021/jm4016894Google ScholarThere is no corresponding record for this reference.
- 20van Koningsbruggen-Rietschel, S.; Conrath, K.; Fischer, R.; Sutharsan, S.; Kempa, A.; Gleiber, W.; Schwarz, C.; Hector, A.; Van Osselaer, N.; Pano, A.; Corveleyn, S.; Bwirire, D.; Santermans, E.; Muller, K.; Bellaire, S.; Van de Steen, O. GLPG2737 in lumacaftor/ivacaftor-treated CF subjects homozygous for the F508del mutation: A randomized phase 2A trial (PELICAN). J. Cyst. Fibros. 2020, 19 (2), 292– 298, DOI: 10.1016/j.jcf.2019.09.006Google ScholarThere is no corresponding record for this reference.
- 21Van der Plas, S. E.; Kelgtermans, H.; Mammoliti, O.; Menet, C.; Tricarico, G.; De Blieck, A.; Joannesse, C.; De Munck, T.; Lambin, D.; Cowart, M.; Dropsit, S.; Martina, S. L. X.; Gees, M.; Wesse, A. S.; Conrath, K.; Andrews, M. Discovery of GLPG2451, a Novel Once Daily Potentiator for the Treatment of Cystic Fibrosis. J. Med. Chem. 2021, 64 (1), 343– 353, DOI: 10.1021/acs.jmedchem.0c01796Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXitF2qtg%253D%253D&md5=a9568e6a3eebfb7fe4f6ac63a8f804c2Discovery of GLPG2451, a Novel Once Daily Potentiator for the Treatment of Cystic FibrosisVan der Plas, Steven E.; Kelgtermans, Hans; Mammoliti, Oscar; Menet, Christel; Tricarico, Giovanni; De Blieck, Ann; Joannesse, Caroline; De Munck, Tom; Lambin, Dominique; Cowart, Marlon; Dropsit, Sebastien; Martina, Sebastien L. X.; Gees, Maarten; Wesse, Anne-Sophie; Conrath, Katja; Andrews, MartinJournal of Medicinal Chemistry (2021), 64 (1), 343-353CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Cystic fibrosis (CF) is a life-threatening recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Lumacaftor, it has been shown that administration of one or more small mols. can partially restore the CFTR function. Correctors are small mols. that enhance the amt. of CFTR on the cell surface, while potentiators improve the gating function of the CFTR channel. Herein, the discovery and optimization of a novel potentiator series are described. Scaffold hopping, focusing on retaining the different intramol. contacts, was crucial in the whole discovery process to identify a novel series devoid of genotoxic liabilities. From this series, the clin. candidate GLPG2451 was selected based on its pharmacokinetic properties, allowing QD dosing and based on its low CYP induction potential.
- 22Yang, B.; Sonawane, N. D.; Zhao, D.; Somlo, S.; Verkman, A. S. Small-molecule CFTR inhibitors slow cyst growth in polycystic kidney disease. J. Am. Soc. Nephrol. 2008, 19 (7), 1300– 1310, DOI: 10.1681/ASN.2007070828Google ScholarThere is no corresponding record for this reference.
- 23Veit, G.; Bossard, F.; Goepp, J.; Verkman, A. S.; Galietta, L. J. V.; Hanrahan, J. W.; Lukacs, G. L. Proinflammatory cytokine secretion is suppressed by TMEM16A or CFTR channel activity in human cystic fibrosis bronchial epithelia. Mol. Biol. Cell 2012, 23 (21), 4188– 4202, DOI: 10.1091/mbc.e12-06-0424Google ScholarThere is no corresponding record for this reference.
- 24Fulcher, M. L.; Gabriel, S.; Burns, K. A.; Yankaskas, J. R.; Randell, S. H. Well-differentiated human airway epithelial cell cultures. Methods Mol. Med. 2005, 107, 183– 206, DOI: 10.1385/1-59259-861-7:183Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjt1aqtw%253D%253D&md5=5973c67cbf202271f3b666acd2c24653Well-differentiated human airway epithelial cell culturesFulcher, M. Leslie; Gabriel, Sherif; Burns, Kimberlie A.; Yankaskas, James R.; Randell, Scott H.Methods in Molecular Medicine (2005), 107 (Human Cell Culture Protocols), 183-206CODEN: MMMEFN ISSN:. (Humana Press Inc.)Procedures for culturing human airway epithelial cells using two closely related media, bronchial epithelial growth medium (BEGM) and air-liq. interface (ALI) medium, are described. BEGM is used when the initial cell harvests are plated on collagen-coated plastic dishes or to expand passaged cells on plastic. ALI medium is employed to support growth and differentiation on porous supports.
- 25Austin, R. P.; Barton, P.; Mohmed, S.; Riley, R. J. The binding of drugs to hepatocytes and its relationship to physicochemical properties. Drug Metab. Dispos. 2005, 33 (3), 419– 425, DOI: 10.1124/dmd.104.002436Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXisFSgtrs%253D&md5=04e45588f46cab9cdbfd0a84503ffed4The binding of drugs to hepatocytes and its relationship to physicochemical propertiesAustin, Rupert P.; Barton, Patrick; Mohmed, Sarfraz; Riley, Robert J.Drug Metabolism and Disposition (2005), 33 (3), 419-425CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)The binding of 17 drugs to rat hepatocytes was detd. using equil. dialysis in combination with metabolic inhibitors and a kinetic model for the binding and dialysis processes. Metabolic inhibitors were used to retard the main routes of metab. such that the half-life for turnover of the drugs was comparable to or greater than the time scale of the equil. dialysis process. Further expts. were carried out to det. the kinetics of diffusion of the compds. across the dialysis membrane and the obsd. extent of binding to hepatocytes. Knowledge of the rate of metab. of the drugs in the presence of the inhibitors, the kinetics of the dialysis process, and the obsd. extent of binding was then used with a kinetic model of the system to give true free fractions of the drugs in live hepatocytes. Further studies show that, for this set of compds., there is no significant difference in the extent of binding to live or dead hepatocytes. The extent of hepatocyte binding is correlated with lipophilicity, and the best model for binding uses log P for basic compds. and log D7.4 for acidic and neutral compds. Hepatocyte binding is also demonstrated to be highly correlated with microsome binding.
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- Xueqing Wang, Chris Tse, Ashvani Singh. Discovery and Development of CFTR Modulators for the Treatment of Cystic Fibrosis. Journal of Medicinal Chemistry 2025, Article ASAP.
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Abstract
Figure 1
Figure 1. Structures of existing potentiators (1 and 3) and correctors (2, 4, and 5).
Figure 2
Figure 2. Plot of CSE HRP potency (X-axis, EC50 [nM]) and CSE HRP efficacy (Y-axis, % max activation) for acid (red), acylsulfonylurea (blue), and acylsulfonamide (yellow) analogues.
Figure 3
Figure 3. TECC current measurement assay in primary CF derived HBE cells (current induced after FSK stimulation after 24 h of incubation with correctors and potentiators). (A) Dose response of GLPG2737 in combination with 1 μM potentiator GLPG1837 and 0.15 μM corrector 4. (B) Comparison of a dose response for GLPG1837 in combination with 1 μM compound 52 + 0.15 μM C1 corrector 4 or only corrector 4.
Scheme 1
Scheme 1. a
aa) 130–170 °C. 3–40 h, (54a: 67%, 54b: 95%); b) Phenyl dichlorophosphate. 170 °C. 15–21 h, (55a: 75%, 55b: 85%); c) CO(g). Pd(dppf)Cl2.DCM. sodium acetate. 1,4-dioxane. MeOH. 40–60 °C. 2–40 h, (56a: 58%, 56b: 63%); d) Amine. DIPEA or NEt3. MeCN or DMSO. 50–130 °C, (46–94%); e) NaOH or LiOH. H2O. MeOH and/or THF or dioxane. rt to 70 °C, (79–100%); f) EDC.HCl. corresponding nucleophile DMAP. DCM or THF or MeCN. rt. 20 h (30–80%) or CDI. DMF corresponding nucleophile. DBU. Rt (49: 100%, 52: 67%).
References
This article references 25 other publications.
- 1Guo, J.; Garratt, A.; Hill, A. Worldwide rates of diagnosis and effective treatment for cystic fibrosis. J. Cyst. Fibros. 2022, 21 (3), 456– 462, DOI: 10.1016/j.jcf.2022.01.009There is no corresponding record for this reference.
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- 3Bardin, E.; Pastor, A.; Semeraro, M.; Golec, A.; Hayes, K.; Chevalier, B.; Berhal, F.; Prestat, G.; Hinzpeter, A.; Gravier-Pelletier, C.; Pranke, I.; Sermet-Gaudelus, I. Modulators of CFTR. Updates on clinical development and future directions. Eur. J. Med. Chem. 2021, 213, 113195, DOI: 10.1016/j.ejmech.2021.1131953https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXjtVWisLs%253D&md5=347dc40d958b08ffae8e39271a78ca9cModulators of CFTR. Updates on clinical development and future directionsBardin, Emmanuelle; Pastor, Alexandra; Semeraro, Michaela; Golec, Anita; Hayes, Kate; Chevalier, Benoit; Berhal, Farouk; Prestat, Guillaume; Hinzpeter, Alexandre; Gravier-Pelletier, Christine; Pranke, Iwona; Sermet-Gaudelus, IsabelleEuropean Journal of Medicinal Chemistry (2021), 213 (), 113195CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disorder in the Caucasian population. It is due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Current symptomatic CF therapies, which treat the downstream consequences of CFTR mutations, have increased survival. Better knowledge of the CFTR protein has enabled pharmacol. therapy aiming to restore mutated CFTR expression and function. These CFTR "modulators" have revolutionised the CF therapeutic landscape, with the potential to transform prognosis for a considerable no. of patients. This review provides a brief summary of their mechanism of action and presents a thorough review of the results obtained from clin. trials of CFTR modulators.
- 4CFTR1 Database. Available from: http://www.genet.sickkids.on.ca/ (accessed 22 June 2023).There is no corresponding record for this reference.
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- 6Ramsey, B. W.; Davies, J.; McElvaney, N. G.; Tullis, E.; Bell, S. C.; Dřevínek, P.; Griese, M.; McKone, E. F.; Wainwright, C. E.; Konstan, M. W.; Moss, R.; Ratjen, F.; Sermet-Gaudelus, I.; Rowe, S. M.; Dong, Q.; Rodriguez, S.; Yen, K.; Ordoñez, C.; Elborn, J. S. A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation. N. Engl. J. Med. 2011, 365 (18), 1663– 1672, DOI: 10.1056/NEJMoa11051856https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVWqtbbE&md5=c9f4abffc063d6269677eb32dc9a83e8A CFTR potentiator in patients with cystic fibrosis and the G551D mutationRamsey, Bonnie W.; Davis, Jane; McElvaney, Gerard; Tullis, Elizabeth; Bell, Scott C.; Dievinek, Pavel; Griese, Matthias; McKone, Edward F.; Wainwright, Claire E.; Konstan, Michael W.; Moss, Richard; Ratjen, Felix; Sermet-Gaudelus, Isabelle; Rowe, Steven M.; Dong, Qunming; Rodriguez, Sally; Yen, Karl; Ordonez, Claudia; Elborn, J. StuartNew England Journal of Medicine (2011), 365 (18), 1663-1672CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 h (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 wk. The primary end point was the estd. mean change from baseline through week 24 in the percent of predicted forced expiratory vol. in 1 s (FEV1). RESULTS: The change from baseline through week 24 in the percent of predicted FEV1 was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P < 0.001). Effects on pulmonary function were noted by 2 wk, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P < 0.001). In addn., through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire-revised instrument (a 100-point scale, with higher nos. indicating a lower effect of symptoms on the patient's quality of life) (P < 0.001). By 48 wk, patients treated with ivacaftor had gained, on av., 2.7 kg more wt. than had patients receiving placebo (P < 0.001). The change from baseline through week 48 in the concn. of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was -48.1 mmol per L (P < 0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%). CONCLUSIONS: Ivacaftor was assocd. with improvements in lung function at 2 wk that were sustained through 48 wk. Substantial improvements were also obsd. in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, wt., and concn. of sweat chloride.
- 7Hadida, S.; Van Goor, F.; Zhou, J.; Arumugam, V.; McCartney, J.; Hazlewood, A.; Decker, C.; Negulescu, P.; Grootenhuis, P. D. Discovery of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, ivacaftor), a potent and orally bioavailable CFTR potentiator. J. Med. Chem. 2014, 57 (23), 9776– 9795, DOI: 10.1021/jm5012808There is no corresponding record for this reference.
- 8Ren, H. Y.; Grove, D. E.; De La Rosa, O.; Houck, S. A.; Sopha, P.; Van Goor, F.; Hoffman, B. J.; Cyr, D. M. VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol. Biol. Cell 2013, 24 (19), 3016– 3024, DOI: 10.1091/mbc.e13-05-0240There is no corresponding record for this reference.
- 9Heijerman, H. G. M.; McKone, E. F.; Downey, D. G.; Van Braeckel, E.; Rowe, S. M.; Tullis, E.; Mall, M. A.; Welter, J. J.; Ramsey, B. W.; McKee, C. M.; Marigowda, G.; Moskowitz, S. M.; Waltz, D.; Sosnay, P. R.; Simard, C.; Ahluwalia, N.; Xuan, F.; Zhang, Y.; Taylor-Cousar, J. L.; McCoy, K. S. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet 2019, 394 (10212), 1940– 1948, DOI: 10.1016/S0140-6736(19)32597-89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitV2msr%252FF&md5=6e00357faca65805cf40d67eec84dc3fEfficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trialHeijerman, Harry G. M.; McKone, Edward F.; Downey, Damian G.; Van Braeckel, Eva; Rowe, Steven M.; Tullis, Elizabeth; Mall, Marcus A.; Welter, John J.; Ramsey, Bonnie W.; McKee, Charlotte M.; Marigowda, Gautham; Moskowitz, Samuel M.; Waltz, David; Sosnay, Patrick R.; Simard, Christopher; Ahluwalia, Neil; Xuan, Fengjuan; Zhang, Yaohua; Taylor-Cousar, Jennifer L.; McCoy, Karen S.Lancet (2019), 394 (10212), 1940-1948CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addn. of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clin. outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation. This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory vol. in 1 s (ppFEV1) of 40-90%, inclusive. After a 4-wk tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 wk of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h vs. tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the abs. change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were abs. change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548. Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-wk treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concn. (LSM treatment difference -45·1 mmol/L [95% CI -50·1 to -40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor. Elexacaftor plus tezacaftor plus ivacaftor provided clin. robust benefit compared with tezacaftor plus ivacaftor alone, with a favorable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation.Vertex Pharmaceuticals.
- 10de Wilde, G.; Gees, M.; Musch, S.; Verdonck, K.; Jans, M.; Wesse, A. S.; Singh, A. K.; Hwang, T. C.; Christophe, T.; Pizzonero, M.; Van der Plas, S.; Desroy, N.; Cowart, M.; Stouten, P.; Nelles, L.; Conrath, K. Identification of GLPG/ABBV-2737, a Novel Class of Corrector, Which Exerts Functional Synergy With Other CFTR Modulators. Front. Pharmacol. 2019, 10, 514, DOI: 10.3389/fphar.2019.0051410https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVGkt77P&md5=9f4a5c0ab242a599af1bb45c73a88c35Identification of GLPG/ABBV-2737, a novel class of corrector, which exerts functional synergy with other CFTR modulatorsde Wilde, Gert; Gees, Maarten; Musch, Sara; Verdonck, Katleen; Jans, Mia; Wesse, Anne-Sophie; Singh, Ashvani K.; Hwang, Tzyh-Chang; Christophe, Thierry; Pizzonero, Mathieu; Van der Plas, Steven; Desroy, Nicolas; Cowart, Marlon; Stouten, Pieter; Nelles, Luc; Conrath, KatjaFrontiers in Pharmacology (2019), 10 (), 514CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)The deletion of phenylalanine at position 508 (F508del) in cystic fibrosis transmembrane conductance regulator (CFTR) causes a severe defect in folding and trafficking of the chloride channel resulting in its absence at the plasma membrane of epithelial cells leading to cystic fibrosis. Progress in the understanding of the disease increased over the past decades and led to the awareness that combinations of mechanistically different CFTR modulators are required to obtain meaningful clin. benefit. Today, there remains an unmet need for identification and development of more effective CFTR modulator combinations to improve existing therapies for patients carrying the F508del mutation. Here, we describe the identification of a novel F508del corrector using functional assays. We provide exptl. evidence that the clin. candidate GLPG/ABBV-2737 represents a novel class of corrector exerting activity both on its own and in combination with VX809 or GLPG/ABBV-2222.
- 11Davies, J. C.; Van de Steen, O.; van Koningsbruggen-Rietschel, S.; Drevinek, P.; Derichs, N.; McKone, E. F.; Kanters, D.; Allamassey, L.; Namour, F.; de Kock, H.; Conrath, K. GLPG1837, a CFTR potentiator, in p.Gly551Asp (G551D)-CF patients: An open-label, single-arm, phase 2a study (SAPHIRA1). J. Cyst. Fibros. 2019, 18 (5), 693– 699, DOI: 10.1016/j.jcf.2019.05.006There is no corresponding record for this reference.
- 12Bell, S. C.; Barry, P. J.; De Boeck, K.; Drevinek, P.; Elborn, J. S.; Plant, B. J.; Minic, P.; Van Braeckel, E.; Verhulst, S.; Muller, K.; Kanters, D.; Bellaire, S.; de Kock, H.; Geller, D. E.; Conrath, K.; Van de Steen, O.; van der Ent, K. CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials. J. Cyst. Fibros. 2019, 18 (5), 700– 707, DOI: 10.1016/j.jcf.2019.04.01412https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M7isFGntg%253D%253D&md5=68c6243b1f7438e9a61a3bca48618ddcCFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trialsBell Scott C; Barry Peter J; De Boeck Kris; Drevinek Pavel; Elborn J Stuart; Plant Barry J; Minic Predag; Van Braeckel Eva; Verhulst Stijn; Muller Karine; Kanters Desiree; de Kock Herman; Conrath Katja; Van de Steen Olivier; Bellaire Susan; Geller David E; van der Ent KorsJournal of cystic fibrosis : official journal of the European Cystic Fibrosis Society (2019), 18 (5), 700-707 ISSN:.BACKGROUND: Several treatment approaches in cystic fibrosis (CF) aim to correct CF transmembrane conductance regulator (CFTR) function; the efficacy of each approach is dependent on the mutation(s) present. A need remains for more effective treatments to correct functional deficits caused by the F508del mutation. METHODS: Two placebo-controlled, phase 2a studies evaluated GLPG2222, given orally once daily for 29 days, in subjects homozygous for F508del (FLAMINGO) or heterozygous for F508del and a gating mutation, receiving ivacaftor (ALBATROSS). The primary objective of both studies was to assess safety and tolerability. Secondary objectives included assessment of pharmacokinetics, and of the effect of GLPG2222 on sweat chloride concentrations, pulmonary function and respiratory symptoms. RESULTS: Fifty-nine and 37 subjects were enrolled into FLAMINGO and ALBATROSS, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.2% (14/48) of subjects in FLAMINGO and 40.0% (12/30) in ALBATROSS; most were mild to moderate in severity and comprised primarily respiratory, gastrointestinal, and infection events. There were no deaths or discontinuations due to TEAEs. Dose-dependent decreases in sweat chloride concentrations were seen in GLPG2222-treated subjects (maximum decrease in FLAMINGO: -17.6 mmol/L [GLPG2222 200 mg], p < 0.0001; ALBATROSS: -7.4 mmol/L [GLPG2222 300 mg], p < 0.05). No significant effects on pulmonary function or respiratory symptoms were reported. Plasma GLPG2222 concentrations in CF subjects were consistent with previous studies in healthy volunteers and CF subjects. CONCLUSIONS: GLPG2222 was well tolerated. Sweat chloride reductions support on-target enhancement of CFTR activity in subjects with F508del mutation(s). Significant improvements in clinical endpoints were not demonstrated. Observed safety results support further evaluation of GLPG2222, including in combination with other CFTR modulators. FUNDING: Galapagos NV. Clinical trial registration numbers FLAMINGO, NCT03119649; ALBATROSS, NCT03045523.
- 13Singh, A. K.; Fan, Y.; Balut, C.; Alani, S.; Manelli, A. M.; Swensen, A. M.; Jia, Y.; Neelands, T. R.; Vortherms, T. A.; Liu, B.; Searle, X. B.; Wang, X.; Gao, W.; Hwang, T. C.; Ren, H. Y.; Cyr, D.; Kym, P. R.; Conrath, K.; Tse, C. Biological Characterization of F508delCFTR Protein Processing by the CFTR Corrector ABBV-2222/GLPG2222. J. Pharmacol. Exp. Ther. 2020, 372 (1), 107– 118, DOI: 10.1124/jpet.119.261800There is no corresponding record for this reference.
- 14Bredael, K.; Geurs, S.; Clarisse, D.; De Bosscher, K.; D’hooghe, M. Carboxylic Acid Bioisosteres in Medicinal Chemistry: Synthesis and Properties. J. Chem. 2022, 2022, 2164558, DOI: 10.1155/2022/2164558There is no corresponding record for this reference.
- 15Smith, D. A.; Beaumont, K.; Maurer, T. S.; Di, L. Volume of Distribution in Drug Design. J. Med. Chem. 2015, 58 (15), 5691– 5698, DOI: 10.1021/acs.jmedchem.5b0020115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXltFSlsb0%253D&md5=2c7289b3602a8edef2d9ef0e6a82e483Volume of Distribution in Drug DesignSmith, Dennis A.; Beaumont, Kevin; Maurer, Tristan S.; Di, LiJournal of Medicinal Chemistry (2015), 58 (15), 5691-5698CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Vol. of distribution is one of the most important pharmacokinetic properties of a drug candidate. It is a major determinant of half-life and dosing frequency of a drug. For a similar log P, a basic mol. will tend to exhibit higher vol. of distribution than a neutral mol. Acids often exhibit low vols. of distribution. Although a design strategy against vol. of distribution can be advantageous in achieving desirable dosing regimen, it must be well-directed in order to avoid detrimental effects to other important properties. Strategies to increase vol. of distribution include adding lipophilicity and introducing basic functional groups in a way that does not increase metabolic clearance.
- 16Di, L.; Breen, C.; Chambers, R.; Eckley, S. T.; Fricke, R.; Ghosh, A.; Harradine, P.; Kalvass, J. C.; Ho, S.; Lee, C. A.; Marathe, P.; Perkins, E. J.; Qian, M.; Tse, S.; Yan, Z.; Zamek-Gliszczynski, M. J. Industry Perspective on Contemporary Protein-Binding Methodologies: Considerations for Regulatory Drug-Drug Interaction and Related Guidelines on Highly Bound Drugs. J. Pharm. Sci. 2017, 106 (12), 3442– 3452, DOI: 10.1016/j.xphs.2017.09.00516https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1Gmu7nO&md5=316d6854cc04968107b609a9ccae6eedIndustry Perspective on Contemporary Protein-Binding Methodologies: Considerations for Regulatory Drug-Drug Interaction and Related Guidelines on Highly Bound DrugsDi, Li; Breen, Christopher; Chambers, Rob; Eckley, Sean T.; Fricke, Robert; Ghosh, Avijit; Harradine, Paul; Kalvass, J. Cory; Ho, Stacy; Lee, Caroline A.; Marathe, Punit; Perkins, Everett J.; Qian, Mark; Tse, Susanna; Yan, Zhengyin; Zamek-Gliszczynski, Maciej J.Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2017), 106 (12), 3442-3452CODEN: JPMSAE; ISSN:0022-3549. (Elsevier Inc.)A review. Regulatory agencies have recently issued drug-drug interaction guidelines, which require detn. of plasma protein binding (PPB). To err on the conservative side, the agencies recommend that a 0.01 lower limit of fraction unbound (fu) be used for highly bound compds. (>99%), irresp. of the actual measured values. While this may avoid false negatives, the recommendation would likely result in a high rate of false pos. predictions, resulting in unnecessary clin. studies and more stringent inclusion/exclusion criteria, which may add cost and time in delivery of new medicines to patients. In this perspective, the authors provide a review of current approaches to measure PPB, and important determinants in enabling the accuracy and precision in these measurements. The ability to measure fu is further illustrated by a cross-company data comparison of PPB for warfarin and itraconazole, demonstrating good concordance of the measured fu values. The data indicate that fu values of ≤0.01 may be detd. accurately across labs. when appropriate methods are used. These data, along with numerous other examples presented in the literature, support the use of exptl. measured fu values for drug-drug interaction predictions, rather than using the arbitrary cutoff value of 0.01 as recommended in current regulatory guidelines.
- 17Davies, M.; Jones, R. D. O.; Grime, K.; Jansson-Lofmark, R.; Fretland, A. J.; Winiwarter, S.; Morgan, P.; McGinnity, D. F. Improving the Accuracy of Predicted Human Pharmacokinetics: Lessons Learned from the AstraZeneca Drug Pipeline Over Two Decades. Trends Pharmacol. Sci. 2020, 41 (6), 390– 408, DOI: 10.1016/j.tips.2020.03.00417https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXntlSisb0%253D&md5=59e5d969ba3de23dc522ab5d2ab14801Improving the Accuracy of Predicted Human Pharmacokinetics: Lessons Learned from the AstraZeneca Drug Pipeline Over Two DecadesDavies, Michael; Jones, Rhys D. O.; Grime, Ken; Jansson-Lofmark, Rasmus; Fretland, Adrian J.; Winiwarter, Susanne; Morgan, Paul; McGinnity, Dermot F.Trends in Pharmacological Sciences (2020), 41 (6), 390-408CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)During drug discovery and prior to the first human dose of a novel candidate drug, the pharmacokinetic (PK) behavior of the drug in humans is predicted from preclin. data. This helps to inform the likelihood of achieving therapeutic exposures in early clin. development. Once clin. data are available, the obsd. human PK are compared with predictions, providing an opportunity to assess and refine prediction methods. Application of best practice in exptl. data generation and predictive methodologies, and a focus on robust mechanistic understanding of the candidate drug disposition properties before nomination to clin. development, have led to maximizing the probability of successful PK predictions so that 83% of AstraZeneca drug development projects progress in the clinic with no PK issues; and 71% of key PK parameter predictions [64% of area under the curve (AUC) predictions; 78% of max. concn. (Cmax) predictions; and 70% of half-life predictions] are accurate to within twofold. Here, we discuss methods to predict human PK used by AstraZeneca, how these predictions are assessed and what can be learned from evaluating the predictions for 116 candidate drugs.
- 18Lassalas, P.; Gay, B.; Lasfargeas, C.; James, M. J.; Tran, V.; Vijayendran, K. G.; Brunden, K. R.; Kozlowski, M. C.; Thomas, C. J.; Smith, A. B.; Huryn, D. M.; Ballatore, C. Structure Property Relationships of Carboxylic Acid Isosteres. J. Med. Chem. 2016, 59 (7), 3183– 3203, DOI: 10.1021/acs.jmedchem.5b0196318https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktFartbY%253D&md5=34490fc72fdb321d8c9751bef1bf79c5Structure Property Relationships of Carboxylic Acid IsosteresLassalas, Pierrik; Gay, Bryant; Lasfargeas, Caroline; James, Michael J.; Tran, Van; Vijayendran, Krishna G.; Brunden, Kurt R.; Kozlowski, Marisa C.; Thomas, Craig J.; Smith, Amos B.; Huryn, Donna M.; Ballatore, CarloJournal of Medicinal Chemistry (2016), 59 (7), 3183-3203CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The replacement of a carboxylic acid with a surrogate structure, or (bio)-isostere, is a classical strategy in medicinal chem. The general underlying principle is that by maintaining the features of the carboxylic acid crit. for biol. activity, but appropriately modifying the physicochem. properties, improved analogs may result. In this context, a systematic assessment of the physicochem. properties of carboxylic acid isosteres would be desirable to enable more informed decisions of potential replacements to be used for analog design. Herein we report the structure-property relationships (SPR) of 35 phenylpropionic acid derivs., in which the carboxylic acid moiety is replaced with a series of known isosteres. The data set generated provides an assessment of the relative impact on the physicochem. properties that these replacements may have compared to the carboxylic acid analog. As such, this study presents a framework for how to rationally apply isosteric replacements of the carboxylic acid functional group.
- 19Gentles, R. G.; Ding, M.; Bender, J. A.; Bergstrom, C. P.; Grant-Young, K.; Hewawasam, P.; Hudyma, T.; Martin, S.; Nickel, A.; Regueiro-Ren, A.; Tu, Y.; Yang, Z.; Yeung, K. S.; Zheng, X.; Chao, S.; Sun, J. H.; Beno, B. R.; Camac, D. M.; Chang, C. H.; Gao, M.; Morin, P. E.; Sheriff, S.; Tredup, J.; Wan, J.; Witmer, M. R.; Xie, D.; Hanumegowda, U.; Knipe, J.; Mosure, K.; Santone, K. S.; Parker, D. D.; Zhuo, X.; Lemm, J.; Liu, M.; Pelosi, L.; Rigat, K.; Voss, S.; Wang, Y.; Wang, Y. K.; Colonno, R. J.; Gao, M.; Roberts, S. B.; Gao, Q.; Ng, A.; Meanwell, N. A.; Kadow, J. F. Discovery and preclinical characterization of the cyclopropylindolobenzazepine BMS-791325, a potent allosteric inhibitor of the hepatitis C virus NS5B polymerase. J. Med. Chem. 2014, 57 (5), 1855– 1879, DOI: 10.1021/jm4016894There is no corresponding record for this reference.
- 20van Koningsbruggen-Rietschel, S.; Conrath, K.; Fischer, R.; Sutharsan, S.; Kempa, A.; Gleiber, W.; Schwarz, C.; Hector, A.; Van Osselaer, N.; Pano, A.; Corveleyn, S.; Bwirire, D.; Santermans, E.; Muller, K.; Bellaire, S.; Van de Steen, O. GLPG2737 in lumacaftor/ivacaftor-treated CF subjects homozygous for the F508del mutation: A randomized phase 2A trial (PELICAN). J. Cyst. Fibros. 2020, 19 (2), 292– 298, DOI: 10.1016/j.jcf.2019.09.006There is no corresponding record for this reference.
- 21Van der Plas, S. E.; Kelgtermans, H.; Mammoliti, O.; Menet, C.; Tricarico, G.; De Blieck, A.; Joannesse, C.; De Munck, T.; Lambin, D.; Cowart, M.; Dropsit, S.; Martina, S. L. X.; Gees, M.; Wesse, A. S.; Conrath, K.; Andrews, M. Discovery of GLPG2451, a Novel Once Daily Potentiator for the Treatment of Cystic Fibrosis. J. Med. Chem. 2021, 64 (1), 343– 353, DOI: 10.1021/acs.jmedchem.0c0179621https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXitF2qtg%253D%253D&md5=a9568e6a3eebfb7fe4f6ac63a8f804c2Discovery of GLPG2451, a Novel Once Daily Potentiator for the Treatment of Cystic FibrosisVan der Plas, Steven E.; Kelgtermans, Hans; Mammoliti, Oscar; Menet, Christel; Tricarico, Giovanni; De Blieck, Ann; Joannesse, Caroline; De Munck, Tom; Lambin, Dominique; Cowart, Marlon; Dropsit, Sebastien; Martina, Sebastien L. X.; Gees, Maarten; Wesse, Anne-Sophie; Conrath, Katja; Andrews, MartinJournal of Medicinal Chemistry (2021), 64 (1), 343-353CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Cystic fibrosis (CF) is a life-threatening recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Lumacaftor, it has been shown that administration of one or more small mols. can partially restore the CFTR function. Correctors are small mols. that enhance the amt. of CFTR on the cell surface, while potentiators improve the gating function of the CFTR channel. Herein, the discovery and optimization of a novel potentiator series are described. Scaffold hopping, focusing on retaining the different intramol. contacts, was crucial in the whole discovery process to identify a novel series devoid of genotoxic liabilities. From this series, the clin. candidate GLPG2451 was selected based on its pharmacokinetic properties, allowing QD dosing and based on its low CYP induction potential.
- 22Yang, B.; Sonawane, N. D.; Zhao, D.; Somlo, S.; Verkman, A. S. Small-molecule CFTR inhibitors slow cyst growth in polycystic kidney disease. J. Am. Soc. Nephrol. 2008, 19 (7), 1300– 1310, DOI: 10.1681/ASN.2007070828There is no corresponding record for this reference.
- 23Veit, G.; Bossard, F.; Goepp, J.; Verkman, A. S.; Galietta, L. J. V.; Hanrahan, J. W.; Lukacs, G. L. Proinflammatory cytokine secretion is suppressed by TMEM16A or CFTR channel activity in human cystic fibrosis bronchial epithelia. Mol. Biol. Cell 2012, 23 (21), 4188– 4202, DOI: 10.1091/mbc.e12-06-0424There is no corresponding record for this reference.
- 24Fulcher, M. L.; Gabriel, S.; Burns, K. A.; Yankaskas, J. R.; Randell, S. H. Well-differentiated human airway epithelial cell cultures. Methods Mol. Med. 2005, 107, 183– 206, DOI: 10.1385/1-59259-861-7:18323https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjt1aqtw%253D%253D&md5=5973c67cbf202271f3b666acd2c24653Well-differentiated human airway epithelial cell culturesFulcher, M. Leslie; Gabriel, Sherif; Burns, Kimberlie A.; Yankaskas, James R.; Randell, Scott H.Methods in Molecular Medicine (2005), 107 (Human Cell Culture Protocols), 183-206CODEN: MMMEFN ISSN:. (Humana Press Inc.)Procedures for culturing human airway epithelial cells using two closely related media, bronchial epithelial growth medium (BEGM) and air-liq. interface (ALI) medium, are described. BEGM is used when the initial cell harvests are plated on collagen-coated plastic dishes or to expand passaged cells on plastic. ALI medium is employed to support growth and differentiation on porous supports.
- 25Austin, R. P.; Barton, P.; Mohmed, S.; Riley, R. J. The binding of drugs to hepatocytes and its relationship to physicochemical properties. Drug Metab. Dispos. 2005, 33 (3), 419– 425, DOI: 10.1124/dmd.104.00243624https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXisFSgtrs%253D&md5=04e45588f46cab9cdbfd0a84503ffed4The binding of drugs to hepatocytes and its relationship to physicochemical propertiesAustin, Rupert P.; Barton, Patrick; Mohmed, Sarfraz; Riley, Robert J.Drug Metabolism and Disposition (2005), 33 (3), 419-425CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)The binding of 17 drugs to rat hepatocytes was detd. using equil. dialysis in combination with metabolic inhibitors and a kinetic model for the binding and dialysis processes. Metabolic inhibitors were used to retard the main routes of metab. such that the half-life for turnover of the drugs was comparable to or greater than the time scale of the equil. dialysis process. Further expts. were carried out to det. the kinetics of diffusion of the compds. across the dialysis membrane and the obsd. extent of binding to hepatocytes. Knowledge of the rate of metab. of the drugs in the presence of the inhibitors, the kinetics of the dialysis process, and the obsd. extent of binding was then used with a kinetic model of the system to give true free fractions of the drugs in live hepatocytes. Further studies show that, for this set of compds., there is no significant difference in the extent of binding to live or dead hepatocytes. The extent of hepatocyte binding is correlated with lipophilicity, and the best model for binding uses log P for basic compds. and log D7.4 for acidic and neutral compds. Hepatocyte binding is also demonstrated to be highly correlated with microsome binding.
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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c01790.
Supplemental PK tables; general methods for compound synthesis/analysis, general methods for synthesis of intermediates, and experimental procedure for the synthesis of intermediates and compounds 8–52; HPLC traces of compounds 8–52 (PDF)
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