ACS Publications. Most Trusted. Most Cited. Most Read

OR SEARCH CITATIONS

My Activity
Publications
CONTENT TYPES

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2005, 48, 23, 7089-7092
RETURN TO ISSUELetterNEXT

7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4- triazol-3-ylmethoxy)-3-(2-fluorophenyl)- 1,2,4-triazolo[4,3-b]pyridazine:  A Functionally Selective γ-Aminobutyric AcidA (GABAA) α2/α3-Subtype Selective Agonist That Exhibits Potent Anxiolytic Activity but Is Not Sedating in Animal Models

View Author Information
Departments of Medicinal Chemistry, Biochemistry, and Pharmacology, Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
Cite this: J. Med. Chem. 2005, 48, 23, 7089–7092
Publication Date (Web):October 14, 2005
https://doi.org/10.1021/jm058034a
Copyright © 2005 American Chemical Society
Request reuse permissions

    Article Views

    1794

    Altmetric

    -

    Citations

    45
    LEARN ABOUT THESE METRICS
    Read OnlinePDF (98 KB)
    Get e-Alerts
    Supporting Info (1)»
    SUBJECTS:

    Abstract

    Abstract Image

    There is increasing evidence that compounds with selectivity for γ-aminobutyric acidA (GABAA) α2- and/or α3-subtypes may retain the desirable anxiolytic activity of nonselective benzodiazepines but possess an improved side effect profile. Herein we describe a novel series of GABAA α2/α3 subtype-selective agonists leading to the identification of the development candidate 17, a nonsedating anxiolytic in preclinical animal assays.

    *

     To whom correspondence should be addressed. For R. C.:  phone, (+1279) 440000; fax, (+1279) 440187; e-mail, [email protected]. For J.L.C.:  phone, (+1279) 440000; fax, (+1279) 440187; e-mail, [email protected]. For L.J.S.:  phone, (+1279) 440000; fax, (+1279) 440187; e-mail, [email protected].

    Supporting Information Available

    ARTICLE SECTIONS
    Jump To

    Experimental procedures for synthesis and characterization of intermediates and final products. This material is available free of charge via the Internet at http://pubs.acs.org.

    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.

    Cited By

    This article is cited by 45 publications.

    1. Samuele Maramai, Mohamed Benchekroun, Simon E. Ward, John R. Atack. Subtype Selective γ-Aminobutyric Acid Type A Receptor (GABAAR) Modulators Acting at the Benzodiazepine Binding Site: An Update. Journal of Medicinal Chemistry 2020, 63 (7) , 3425-3446. https://doi.org/10.1021/acs.jmedchem.9b01312
    2. Simon C. Goodacre,, Leslie J. Street,, David J. Hallett,, James M. Crawforth,, Sarah Kelly,, Andrew P. Owens,, Wesley P. Blackaby,, Richard T. Lewis,, Joanna Stanley,, Alison J. Smith,, Pushpinder Ferris,, Bindi Sohal,, Susan M. Cook,, Andrew Pike,, Nicola Brown,, Keith A. Wafford,, George Marshall,, José L. Castro, and, John R. Atack. Imidazo[1,2-a]pyrimidines as Functionally Selective and Orally Bioavailable GABAAα2/α3 Binding Site Agonists for the Treatment of Anxiety Disorders. Journal of Medicinal Chemistry 2006, 49 (1) , 35-38. https://doi.org/10.1021/jm051065l
    3. Ab Majeed Ganai, Tabasum Khan Pathan, Sachin Balaso Mohite, Veronika Vojáčková, Eva Řezníčková, Karolína Kozlanská, Vladimír Kryštof, Katya Govender, Sithabile Mokoena, Srinivas Reddy Merugu, Mahesh Palkar, Kimeshni Moodley, Rajshekhar Karpoormath. Design and synthesis of novel 1,2,4-triazolo[4,3-b]pyridazine derivatives with anti-cancer activity. Journal of Molecular Structure 2023, 1291 , 135938. https://doi.org/10.1016/j.molstruc.2023.135938
    4. Nicholas A. Meanwell. The pyridazine heterocycle in molecular recognition and drug discovery. Medicinal Chemistry Research 2023, 32 (9) , 1853-1921. https://doi.org/10.1007/s00044-023-03035-9
    5. Rok Cerne, Arnold Lippa, Michael M. Poe, Jodi L. Smith, Xiaoming Jin, Xingjie Ping, Lalit K. Golani, James M. Cook, Jeffrey M. Witkin. GABAkines – Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors. Pharmacology & Therapeutics 2022, 234 , 108035. https://doi.org/10.1016/j.pharmthera.2021.108035
    6. Mathijs B. van der Lei, R. Frank Kooy. Therapeutic potential of GABA A receptor subunit expression abnormalities in fragile X syndrome. Expert Review of Precision Medicine and Drug Development 2022, 7 (1) , 105-120. https://doi.org/10.1080/23808993.2021.2008168
    7. Blanca Angelica Vega Alanis, Maria Teresa Iorio, Luca L. Silva, Konstantina Bampali, Margot Ernst, Michael Schnürch, Marko D. Mihovilovic. Allosteric GABAA Receptor Modulators—A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility. Molecules 2020, 25 (4) , 999. https://doi.org/10.3390/molecules25040999
    8. C.J. Weir, S.J. Mitchell, J.J. Lambert. Role of GABAA receptor subtypes in the behavioural effects of intravenous general anaesthetics. British Journal of Anaesthesia 2017, 119 , i167-i175. https://doi.org/10.1093/bja/aex369
    9. István Ling, Balázs Mihalik, Lori-An Etherington, Gábor Kapus, Adrienn Pálvölgyi, Gábor Gigler, Szabolcs Kertész, Attila Gaál, Katalin Pallagi, Péter Kiricsi, Éva Szabó, Gábor Szénási, Lilla Papp, László G. Hársing, György Lévay, Michael Spedding, Jeremy J. Lambert, Delia Belelli, József Barkóczy, Balázs Volk, Gyula Simig, István Gacsályi, Ferenc A. Antoni. A novel GABAA alpha 5 receptor inhibitor with therapeutic potential. European Journal of Pharmacology 2015, 764 , 497-507. https://doi.org/10.1016/j.ejphar.2015.07.005
    10. Z. Arghiani, S. M. Seyedi, M. Bakavoli, H. Eshghi. Facile Synthesis of New [1,2,4]Triazolo[4,3‐ b ]pyridazine. Journal of Heterocyclic Chemistry 2015, 52 (4) , 1099-1107. https://doi.org/10.1002/jhet.2207
    11. M. Wang, Y. Li, Y. Lin. GABAA receptor α2 subtype activation suppresses retinal spreading depression. Neuroscience 2015, 298 , 137-144. https://doi.org/10.1016/j.neuroscience.2015.04.016
    12. Edward P. Christian, Dean H. Snyder, Wei Song, David A. Gurley, Joanne Smolka, Donna L. Maier, Min Ding, Farzin Gharahdaghi, Xiaodong F. Liu, Maninder Chopra, Maria Ribadeneira, Marc J. Chapdelaine, Adam Dudley, Jeffrey L. Arriza, Carla Maciag, Michael C. Quirk, James J. Doherty. EEG-β/γ spectral power elevation in rat: a translatable biomarker elicited by GABA Aα2/3 -positive allosteric modulators at nonsedating anxiolytic doses. Journal of Neurophysiology 2015, 113 (1) , 116-131. https://doi.org/10.1152/jn.00539.2013
    13. Ryan F Yoshimura, Minhtam B Tran, Derk J Hogenkamp, Timothy B Johnstone, Jennifer Y Xie, Frank Porreca, Kelvin W Gee. Limited central side effects of a β-subunit subtype-selective GABA A receptor allosteric modulator. Journal of Psychopharmacology 2014, 28 (5) , 472-478. https://doi.org/10.1177/0269881113507643
    14. Gordon Munro, Rikke R. Hansen, Naheed R. Mirza. GABAA receptor modulation: Potential to deliver novel pain medicines?. European Journal of Pharmacology 2013, 716 (1-3) , 17-23. https://doi.org/10.1016/j.ejphar.2013.01.070
    15. Bruce N. Rogers, David L. Gray. Treating the Cognitive Deficits of Schizophrenia. 2012, 123-156. https://doi.org/10.1039/9781849734943-00123
    16. Gordon Munro, Helle K. Erichsen, Mark G. Rae, Naheed R. Mirza. A question of balance – Positive versus negative allosteric modulation of GABAA receptor subtypes as a driver of analgesic efficacy in rat models of inflammatory and neuropathic pain. Neuropharmacology 2011, 61 (1-2) , 121-132. https://doi.org/10.1016/j.neuropharm.2011.03.017
    17. JR Atack, KA Wafford, LJ Street, GR Dawson, S Tye, K Van Laere, G Bormans, SM Sanabria-Bohórquez, I De Lepeleire, JN de Hoon, A Van Hecken, HD Burns, RM McKernan, MG Murphy, RJ Hargreaves. MRK-409 (MK-0343), a GABA A receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans. Journal of Psychopharmacology 2011, 25 (3) , 314-328. https://doi.org/10.1177/0269881109354927
    18. Rajeev Kharb, Prabodh Chander Sharma, Mohammed Shahar Yar. Pharmacological significance of triazole scaffold. Journal of Enzyme Inhibition and Medicinal Chemistry 2011, 26 (1) , 1-21. https://doi.org/10.3109/14756360903524304
    19. Ryan W Lewis, George P Hess, Bruce Ganem. Use of multicomponent reactions in developing small-molecule tools to study GABA A receptor mechanism and function. Future Medicinal Chemistry 2011, 3 (2) , 243-250. https://doi.org/10.4155/fmc.10.302
    20. Matthew A. J. Duncton. Minisci reactions: Versatile CH-functionalizations for medicinal chemists. MedChemComm 2011, 2 (12) , 1135. https://doi.org/10.1039/c1md00134e
    21. Nanda Ghoshal, R Suyambu Kesava Vijayan. Pharmacophore models for GABA A modulators: implications in CNS drug discovery. Expert Opinion on Drug Discovery 2010, 5 (5) , 441-460. https://doi.org/10.1517/17460441003789363
    22. John R. Atack. Preclinical and clinical pharmacology of the GABAA receptor α5 subtype-selective inverse agonist α5IA. Pharmacology & Therapeutics 2010, 125 (1) , 11-26. https://doi.org/10.1016/j.pharmthera.2009.09.001
    23. John R. Atack, Dean F. Wong, Tim D. Fryer, Christine Ryan, Sandra Sanabria, Yun Zhou, Robert F. Dannals, Wai-si Eng, Raymond E. Gibson, H. Donald Burns, Jose M. Vega, Laura Vessy, Paul Scott-Stevens, John S. Beech, Jean-Claude Baron, Bindi Sohal, Michael L. Schrag, Franklin I. Aigbirhio, Ruth M. McKernan, Richard J. Hargreaves. Benzodiazepine Binding Site Occupancy by the Novel GABA A Receptor Subtype-Selective Drug 7-(1,1-Dimethylethyl)-6-(2-ethyl- 2H -1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3- b ]pyridazine (TPA023) in Rats, Primates, and Humans. Journal of Pharmacology and Experimental Therapeutics 2010, 332 (1) , 17-25. https://doi.org/10.1124/jpet.109.157909
    24. Nancy A. Ator, John R. Atack, Richard J. Hargreaves, H. Donald Burns, Gerard R. Dawson. Reducing Abuse Liability of GABA A /Benzodiazepine Ligands via Selective Partial Agonist Efficacy at α 1 and α 2/3 Subtypes. Journal of Pharmacology and Experimental Therapeutics 2010, 332 (1) , 4-16. https://doi.org/10.1124/jpet.109.158303
    25. Amanda P. Skoumbourdis, Christopher A. LeClair, Eduard Stefan, Adrian G. Turjanski, William Maguire, Steven A. Titus, Ruili Huang, Douglas S. Auld, James Inglese, Christopher P. Austin, Stephen W. Michnick, Menghang Xia, Craig J. Thomas. Exploration and optimization of substituted triazolothiadiazines and triazolopyridazines as PDE4 inhibitors. Bioorganic & Medicinal Chemistry Letters 2009, 19 (13) , 3686-3692. https://doi.org/10.1016/j.bmcl.2009.01.057
    26. John Evenden, Laurie Ross, Gerald Jonak, Jin Zhou. A novel operant conflict procedure using incrementing shock intensities to assess the anxiolytic and anxiogenic effects of drugs. Behavioural Pharmacology 2009, 20 (3) , 226-236. https://doi.org/10.1097/FBP.0b013e32832a8110
    27. John R. Atack. GABAA Receptor α2/α3 Subtype-Selective Modulators as Potential Nonsedating Anxiolytics. 2009, 331-360. https://doi.org/10.1007/7854_2009_30
    28. John R. Atack. Subtype-Selective GABAA Receptor Modulation Yields a Novel Pharmacological Profile: The Design and Development of TPA023. 2009, 137-185. https://doi.org/10.1016/S1054-3589(08)57004-9
    29. Dmytro Berezhnoy, Maria C Gravielle, Scott Downing, Emmanuel Kostakis, Anthony S Basile, Phil Skolnick, Terrell T Gibbs, David H Farb. Pharmacological Properties of DOV 315,090, an ocinaplon metabolite. BMC Pharmacology 2008, 8 (1) https://doi.org/10.1186/1471-2210-8-11
    30. R.S.K. Vijayan, Nanda Ghoshal. Structural basis for ligand recognition at the benzodiazepine binding site of GABAA α3 receptor, and pharmacophore-based virtual screening approach. Journal of Molecular Graphics and Modelling 2008, 27 (3) , 286-298. https://doi.org/10.1016/j.jmgm.2008.05.003
    31. Ahmed H. Shamroukh, Mohamed. A. Ali. Anti‐HAV Activity of Some Newly Synthesized Triazolo[4,3‐ b ]pyridazines. Archiv der Pharmazie 2008, 341 (4) , 223-230. https://doi.org/10.1002/ardp.200700181
    32. John R. Atack. GABA A Receptor Subtype‐Selective Efficacy: TPA023, an α2/α3 Selective Non‐sedating Anxiolytic and α5IA, an α5 Selective Cognition Enhancer. CNS Neuroscience & Therapeutics 2008, 14 (1) , 25-35. https://doi.org/10.1111/j.1527-3458.2007.00034.x
    33. John R. Atack. GABA A Receptor Subtype-Selective Efficacy: TPA023, an α2/α3 Selective Non-sedating Anxiolytic and α5IA, an α5 Selective Cognition Enhancer. CNS Neuroscience & Therapeutics 2008, 14 (1) , 25-35. https://doi.org/10.1111/j.1755-5949.2007.00034.x
    34. G. Hajós, Z. Riedl. Bicyclic 5-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1. 2008, 671-763. https://doi.org/10.1016/B978-008044992-0.01016-6
    35. Michael P. Groziak. Chapter 6.2 (2005) Six-membered ring systems: diazines and benzo derivatives (2005). 2008, 353-382. https://doi.org/10.1016/S0959-6380(08)80015-3
    36. S.L. de Haas, S.J. de Visser, J.P. van der Post, R.C. Schoemaker, K. van Dyck, M.G. Murphy, M. de Smet, L.K. Vessey, R. Ramakrishnan, L. Xue, A.F. Cohen, J.M.A. van Gerven. Pharmacodynamic and pharmacokinetic effects of MK-0343, a GABA A α 2,3 subtype selective agonist, compared to lorazepam and placebo in healthy male volunteers. Journal of Psychopharmacology 2008, 22 (1) , 24-32. https://doi.org/10.1177/0269881107082108
    37. Bennett Ma, Stacey L. Polsky-Fisher, Stanley Vickers, Donghui Cui, A. David Rodrigues. Cytochrome P450 3A-Dependent Metabolism of a Potent and Selective γ-Aminobutyric Acid Aα2/3 Receptor Agonist in Vitro: Involvement of Cytochrome P450 3A5 Displaying Biphasic Kinetics. Drug Metabolism and Disposition 2007, 35 (8) , 1301-1307. https://doi.org/10.1124/dmd.107.014753
    38. Rosa L. Fradley, Martin R. Guscott, Sharlene Bull, David J. Hallett, Simon C. Goodacre, Keith A. Wafford, ELizabeth M. Garrett, Richard J. Newman, Gillian F. O'Meara, Paul J. Whiting, Thomas W. Rosahl, Gerard R. Dawson, David S. Reynolds, John R. Atack. Differential contribution of GABA A receptor subtypes to the anticonvulsant efficacy of benzodiazepine site ligands. Journal of Psychopharmacology 2007, 21 (4) , 384-391. https://doi.org/10.1177/0269881106067255
    39. S.L. de Haas, S.J. de Visser, J.P. van der Post, M. de Smet, R.C. Schoemaker, B. Rijnbeek, A.F. Cohen, J.M. Vega, N.G.B. Agrawal, T.V. Goel, R.C. Simpson, L.K. Pearson, S. Li, M. Hesney, M.G. Murphy, J.M.A. van Gerven. Pharmacodynamic and pharmacokinetic effects of TPA023, a GABA A α 2,3 subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers. Journal of Psychopharmacology 2007, 21 (4) , 374-383. https://doi.org/10.1177/0269881106072343
    40. Gabriella Guerrini, Giovanna Ciciani, Giovanni Cambi, Fabrizio Bruni, Silvia Selleri, François Besnard, Marina Montali, Claudia Martini, Carla Ghelardini, Nicoletta Galeotti, Annarella Costanzo. Novel 3-iodo-8-ethoxypyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide as promising lead for design of α5-inverse agonist useful tools for therapy of mnemonic damage. Bioorganic & Medicinal Chemistry 2007, 15 (7) , 2573-2586. https://doi.org/10.1016/j.bmc.2007.01.053
    41. Anthony S. Basile, Arnold S. Lippa, Phil Skolnick. GABAA receptor modulators as anxioselective anxiolytics. Drug Discovery Today: Therapeutic Strategies 2006, 3 (4) , 475-481. https://doi.org/10.1016/j.ddstr.2006.10.009
    42. Robert W. Carling, Michael G.N. Russell, Kevin W. Moore, Andrew Mitchinson, Alexander Guiblin, Alison Smith, Keith A. Wafford, George Marshall, John R. Atack, Leslie J. Street. 2,3,7-Trisubstituted pyrazolo[1,5-d][1,2,4]triazines: Functionally selective GABAA α3-subtype agonists. Bioorganic & Medicinal Chemistry Letters 2006, 16 (13) , 3550-3554. https://doi.org/10.1016/j.bmcl.2006.03.081
    43. Andrew Mitchinson, Wesley P. Blackaby, Sylvie Bourrain, Robert W. Carling, Richard T. Lewis. Synthesis of pyrido[2,3-d]pyridazines and pyrazino[2,3-d]-pyridazines—novel classes of GABAA receptor benzodiazepine binding site ligands. Tetrahedron Letters 2006, 47 (13) , 2257-2260. https://doi.org/10.1016/j.tetlet.2006.01.084
    44. Rainer Rupprecht, Daniela Eser, Peter Zwanzger, Hans-Jürgen Möller. GABA A receptors as targets for novel anxiolytic drugs. The World Journal of Biological Psychiatry 2006, 7 (4) , 231-237. https://doi.org/10.1080/15622970600868525
    45. John R. Atack, Keith A. Wafford, Spencer J. Tye, Susan M. Cook, Bindi Sohal, Andrew Pike, Cyrille Sur, David Melillo, Linda Bristow, Fran Bromidge, Ian Ragan, Julie Kerby, Les Street, Robert Carling, José L. Castro, Paul Whiting, Gerard R. Dawson, Ruth M. McKernan. TPA023 [7-(1,1-Dimethylethyl)-6-(2-ethyl-2 H -1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3- b ]pyridazine], an Agonist Selective for α2- and α3-Containing GABA A Receptors, Is a Nonsedating Anxiolytic in Rodents and Primates. Journal of Pharmacology and Experimental Therapeutics 2006, 316 (1) , 410-422. https://doi.org/10.1124/jpet.105.089920
    Download PDF

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    MENDELEY PAIRING EXPIRED
    Your Mendeley pairing has expired. Please reconnect