ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
Recently Viewed
You have not visited any articles yet, Please visit some articles to see contents here.
CONTENT TYPES

Discovery of Novel Tricyclic Full Agonists for the G-Protein-Coupled Niacin Receptor 109A with Minimized Flushing in Rats

View Author Information
Departments of Medicinal Chemistry, Cardiovascular Diseases, Pharmacology, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065-0900
* To whom correspondence should be addressed. Address: Merck Research Laboratories, Mail Code RY121-252, P.O. Box 2000, 126 East Lincoln Avenue, Rahway, New Jersey 07065-0900. Phone: (732) 594-1755. Fax: (732) 594-9473. E-mail: [email protected]
†Department of Medicinal Chemistry.
‡Department of Cardiovascular Diseases.
§Department of Pharmacology.
#Department of Drug Metabolism.
Cite this: J. Med. Chem. 2009, 52, 8, 2587–2602
Publication Date (Web):March 23, 2009
https://doi.org/10.1021/jm900151e
Copyright © 2009 American Chemical Society
Article Views
3544
Altmetric
-
Citations
LEARN ABOUT THESE METRICS
Read OnlinePDF (1 MB)
Supporting Info (1)»

Abstract

Abstract Image

Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.

Supporting Information

ARTICLE SECTIONS
Jump To

Experimental procedures for compound preparation, characterization data, biological assay protocols, and LC/MS and 1H NMR spectra. 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. Jinxia Wen, Wenyan Zhao, Xu Gao, Xiaofang Ren, Chunping Dong, Cheli Wang, Li Liu, Jian Li. Synthesis of [1,2,3]Triazolo-[1,5-a]quinoxalin-4(5H)-ones through Photoredox-Catalyzed [3 + 2] Cyclization Reactions with Hypervalent Iodine(III) Reagents. The Journal of Organic Chemistry 2022, 87 (6) , 4415-4423. https://doi.org/10.1021/acs.joc.2c00135
  2. Mary Sexton, William P. Malachowski, Glenn P. A. Yap, Diana Rachii, Greg Feldman, Andrew T. Krasley, Zhilin Chen, My Anh Tran, Kalyn Wiley, Alexandra Matei, Samantha Petersen, Sabrina Tran Tien. Catalytic Enantioselective Birch–Heck Sequence for the Synthesis of Phenanthridinone Derivatives with an All-Carbon Quaternary Stereocenter. The Journal of Organic Chemistry 2022, 87 (2) , 1154-1172. https://doi.org/10.1021/acs.joc.1c02523
  3. Kenneth L. Granberg, Zhong-Qing Yuan, Bo Lindmark, Karl Edman, Johan Kajanus, Anders Hogner, Marcus Malmgren, Gavin O’Mahony, Anneli Nordqvist, Jan Lindberg, Stefan Tångefjord, Michael Kossenjans, Christian Löfberg, Jonas Brånalt, Dongmei Liu, Nidhal Selmi, Grigorios Nikitidis, Peter Nordberg, Ahlke Hayen, Anna Aagaard, Eva Hansson, Majlis Hermansson, Ida Ivarsson, Rasmus Jansson-Löfmark, Ulla Karlsson, Ulrika Johansson, Lena William-Olsson, Judith Hartleib-Geschwindner, Krister Bamberg. Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection. Journal of Medicinal Chemistry 2019, 62 (3) , 1385-1406. https://doi.org/10.1021/acs.jmedchem.8b01523
  4. Jiajie Yan, Fengtao Zhou, Dongguang Qin, Tong Cai, Ke Ding, and Qian Cai . Synthesis of [1,2,3]Triazolo[1,5-a]quinoxalin-4(5H)-ones through Copper-Catalyzed Tandem Reactions of N-(2-Haloaryl)propiolamides with Sodium Azide. Organic Letters 2012, 14 (5) , 1262-1265. https://doi.org/10.1021/ol300114w
  5. Chunliang Lu, Qing Xiao, and Paul E. Floreancig. Stereoselective Synthesis of Spirooxindole Amides through Nitrile Hydrozirconation. Organic Letters 2010, 12 (22) , 5112-5115. https://doi.org/10.1021/ol102246d
  6. Gavin R. Hoffman, Allen M. Schoffstall. Syntheses and Applications of 1,2,3-Triazole-Fused Pyrazines and Pyridazines. Molecules 2022, 27 (15) , 4681. https://doi.org/10.3390/molecules27154681
  7. Archana Kumari Sahu, Subhamoy Biswas, Surjya Kumar Bora, Anil K. Saikia. Synthesis of 3 C -alkylated active methylene substituted 2 H -indazole derivatives via sequential ring opening of donor–acceptor cyclopropanes and reductive cyclization reaction. New Journal of Chemistry 2022, 46 (26) , 12456-12460. https://doi.org/10.1039/D2NJ01801B
  8. Dinesh S. Barak, Dipak J. Dahatonde, Sanjay Batra. Metal‐ and Photoredox‐Catalyst Free Unified Approach for the Synthesis of Azole‐Fused Quinolines via tert ‐Butyl Nitrite‐Mediated Regioselective Annulation. Asian Journal of Organic Chemistry 2022, 11 (4) https://doi.org/10.1002/ajoc.202200057
  9. D. Gouthami, B. Srinivas, M Ravinder. Synthesis of Quinoxlines Containing 1,2,3-Triazoles and Their Anti-Bacterial and Anti-Cancer Activity. Russian Journal of Bioorganic Chemistry 2021, 47 (4) , 882-888. https://doi.org/10.1134/S1068162021040105
  10. Hariom Kumar, Manoj Dhameja, Marziya Rizvi, Preeti Gupta. Progress in the Synthesis of Fused 1,2,3‐Triazoles. ChemistrySelect 2021, 6 (20) , 4889-4947. https://doi.org/10.1002/slct.202100442
  11. Nadale Downer-Riley, Alexa Redway, Roxanne Higgins, Yvette Jackson. Alternative Approach to the 2-Oxopyrano[3,2-c]quinoline Core. HETEROCYCLES 2021, 102 (8) , 1553. https://doi.org/10.3987/COM-19-14115
  12. Yi Wang, Zaixiang Fang, Xiaochuan Chen, Yuanhua Wang. Dirhodium(II)‐Catalyzed C(sp 2 )−H Azidation of Benzaldehydes. Chemistry – A European Journal 2020, 26 (30) , 6805-6811. https://doi.org/10.1002/chem.201905855
  13. Yuriko Miyazawa, Takahiro Yamaguchi, Mitsuhiro Yamaguchi, Keiko Tago, Akihiro Tamura, Daisuke Sugiyama, Takahide Aburatani, Tomohiro Nishizawa, Nobuya Kurikawa, Keita Kono. Discovery of novel pyrrole derivatives as potent agonists for the niacin receptor GPR109A. Bioorganic & Medicinal Chemistry Letters 2020, 30 (10) , 127105. https://doi.org/10.1016/j.bmcl.2020.127105
  14. Lyubov I. Kuznetsova, Alexey O. Chagarovskiy, Irina I. Levina, Victor B. Rybakov, Olga A. Ivanova, Igor V. Trushkov. A simple synthesis of 2-{2-[(arylmethylidene)amino]-indazol-3-yl}malonate esters. Chemistry of Heterocyclic Compounds 2020, 56 (5) , 555-561. https://doi.org/10.1007/s10593-020-02699-0
  15. Narasimharao Mukku, Barnali Maiti. On water catalyst-free synthesis of benzo[ d ]imidazo[2,1- b ] thiazoles and novel N -alkylated 2-aminobenzo[ d ]oxazoles under microwave irradiation. RSC Advances 2020, 10 (2) , 770-778. https://doi.org/10.1039/C9RA08929B
  16. K. Shiva Kumar, Praveen Kumar Naikawadi, Bandari Rajesham, D. Rambabu. Four-component, three-step cascade reaction: an effective synthesis of indazole-fused triazolo[5,1- c ]quinoxalines. New Journal of Chemistry 2019, 43 (11) , 4333-4337. https://doi.org/10.1039/C8NJ06299D
  17. D. Gangaprasad, J. Paul Raj, K. Karthikeyan, R. Rengasamy, J. Elangovan. An Efficient One-Pot Synthesis of 1,2,3-Triazole-Fused Chromenes/Quinolines via Oxidative [3+2] Cycloaddition followed by Reductive Cyclization. Advanced Synthesis & Catalysis 2018, 360 (23) , 4485-4490. https://doi.org/10.1002/adsc.201800908
  18. Sandip Gangadhar Balwe, Kwon Taek Lim, Byung Gwon Cho, Yeon Tae Jeong. A pot-economical and green synthesis of novel (benzo[ d ]imidazo[2,1- b ]thiazol-3-yl)-2H-chromen-2-one in ethanol–PEG-600 under catalyst-free conditions. Tetrahedron 2017, 73 (25) , 3564-3570. https://doi.org/10.1016/j.tet.2017.05.047
  19. Dengke Li, Tingting Mao, Jinbo Huang, Qiang Zhu. A one-pot synthesis of [1,2,3]triazolo[1,5-a]quinoxalines from 1-azido-2-isocyanoarenes with high bond-forming efficiency. Chemical Communications 2017, 53 (7) , 1305-1308. https://doi.org/10.1039/C6CC08543A
  20. Yanjun Xie, Xiangui Chen, Zhen Wang, Huawen Huang, Bing Yi, Guo-Jun Deng. Metal-free oxidative cyclization of 2-aminobenzothiazoles and cyclic ketones enabled by the combination of elemental sulfur and oxygen. Green Chemistry 2017, 19 (18) , 4294-4298. https://doi.org/10.1039/C7GC02014G
  21. Irwan Iskandar Roslan, Kian-Hong Ng, Gaik-Khuan Chuah, Stephan Jaenicke. Reagent-controlled regiodivergent intermolecular cyclization of 2-aminobenzothiazoles with β-ketoesters and β-ketoamides. Beilstein Journal of Organic Chemistry 2017, 13 , 2739-2750. https://doi.org/10.3762/bjoc.13.270
  22. Sandip Gangadhar Balwe, Yeon Tae Jeong. Iron-catalyzed unprecedented formation of benzo[d]imidazo[2,1-b]thiazoles under solvent-free conditions. RSC Advances 2016, 6 (109) , 107225-107232. https://doi.org/10.1039/C6RA24183B
  23. Hye Ran Moon, Jin Yu, Ko Hoon Kim, Jae Nyoung Kim. Synthesis of Pyrazolo[1,5- a ]quinolines from 1-Aryl-5-styrylpyrazoles via Intramolecular Friedel-Crafts Reaction/Aerobic Oxidation. Bulletin of the Korean Chemical Society 2015, 36 (4) , 1189-1195. https://doi.org/10.1002/bkcs.10225
  24. Owk Obulesu, Jagadeesh Babu Nanubolu, Surisetti Suresh. Tandem copper (Cu) catalysed N-arylation–vinylogous nitroaldol condensation of 3,5-disubstituted 4-nitropyrazoles. Organic & Biomolecular Chemistry 2015, 13 (30) , 8232-8240. https://doi.org/10.1039/C5OB01011J
  25. Kevin H. Shaughnessy, Engelbert Ciganek, Rebecca B. DeVasher. Copper-Catalyzed Amination of Aryl and Alkenyl Electrophiles. 2014,,, 1-668. https://doi.org/10.1002/0471264180.or085.01
  26. Jin Woo Lim, Ko Hoon Kim, Se Hee Kim, Jae Nyoung Kim. Synthesis of 1H-benzo[g]indazole derivatives: propargyl–allenyl isomerization and 6π-electrocyclization involving two aromatic π-bonds. Tetrahedron 2014, 70 (38) , 6831-6840. https://doi.org/10.1016/j.tet.2014.07.048
  27. Jun-ya Kato, Ryosuke Ijuin, Hiroshi Aoyama, Tsutomu Yokomatsu. Synthesis of poly-substituted pyrazolo[1,5-a]quinolines through one-pot two component cascade reaction. Tetrahedron 2014, 70 (17) , 2766-2775. https://doi.org/10.1016/j.tet.2014.02.081
  28. N. T. Pokhodylo. Multicomponent and Domino Reactions Leading to 1,2,3-Triazoles. 2014,,, 269-324. https://doi.org/10.1007/7081_2014_122
  29. Barbara Bosier, Emmanuel Hermans. Promises of Biased Signaling in the Development of Improved Therapeutics. 2014,,, 251-292. https://doi.org/10.1016/B978-0-12-411460-9.00008-2
  30. Biswajit Roy, Debashis Mondal, Joydev Hatai, Subhajit Bandyopadhyay. A highly efficient tandem [3 + 2] “click” cycloaddition/6- exo -cyclization strategy for the construction of triazole fused pyrazines. RSC Adv. 2014, 4 (100) , 56952-56956. https://doi.org/10.1039/C4RA12489H
  31. Hao Lin, Dianqing Sun. Recent Synthetic Developments and Applications of the Ullmann Reaction. A Review. Organic Preparations and Procedures International 2013, 45 (5) , 341-394. https://doi.org/10.1080/00304948.2013.816208
  32. Jun-ya Kato, Hiroshi Aoyama, Tsutomu Yokomatsu. Development of a new cascade reaction for convergent synthesis of pyrazolo[1,5-a]quinoline derivatives under transition-metal-free conditions. Organic & Biomolecular Chemistry 2013, 11 (7) , 1171. https://doi.org/10.1039/c2ob27050a
  33. Nicholas W. Y. Wong, Dirk H. Ortgies, Pat Forgione. 2-(Diphenylphosphino)-2′-( N , N -dimethylamino)-biphenyl. 2012,,https://doi.org/10.1002/047084289X.rn01456
  34. Wenyuan Qian, David Winternheimer, Albert Amegadzie, Jennifer Allen. One-pot synthesis of [1,2,3]triazole-fused pyrazinopyridazindione tricycles by a ‘click and activate’ approach. Tetrahedron Letters 2012, 53 (3) , 271-274. https://doi.org/10.1016/j.tetlet.2011.11.030
  35. Xinhai Zhang, Jiong Jia, Chen Ma. A one-pot regioselective synthesis of benzo[d]imidazo[2,1-b]thiazoles. Organic & Biomolecular Chemistry 2012, 10 (39) , 7944. https://doi.org/10.1039/c2ob26211h
  36. Islam A.A.E.-H. Ibrahim, Hitoshi Kurose. β-Arrestin-Mediated Signaling Improves the Efficacy of Therapeutics. Journal of Pharmacological Sciences 2012, 118 (4) , 408-412. https://doi.org/10.1254/jphs.11R10CP
  37. Stefan Offermanns, Steven L. Colletti, Timothy W. Lovenberg, Graeme Semple, Alan Wise, Adriaan P. IJzerman. International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B). Pharmacological Reviews 2011, 63 (2) , 269-290. https://doi.org/10.1124/pr.110.003301
  38. Erin J. Whalen, Sudarshan Rajagopal, Robert J. Lefkowitz. Therapeutic potential of β-arrestin- and G protein-biased agonists. Trends in Molecular Medicine 2011, 17 (3) , 126-139. https://doi.org/10.1016/j.molmed.2010.11.004
  39. Chinmay Chowdhury, Sanjukta Mukherjee, Biswajit Chakraborty, Basudeb Achari. A rapid and facile method for the general synthesis of 3-aryl substituted 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their ring fused analogues. Organic & Biomolecular Chemistry 2011, 9 (16) , 5856. https://doi.org/10.1039/c1ob05255a
  40. Darby Schmidt, Abigail Smenton, Subharekha Raghavan, Hong Shen, Fa-Xiang Ding, Ester Carballo-Jane, Silvi Luell, Tanya Ciecko, Tom G. Holt, Michael Wolff, Andrew Taggart, Larissa Wilsie, Mihajlo Krsmanovic, Ning Ren, Daniel Blom, Kang Cheng, Peggy E. McCann, M.Gerard Waters, James Tata, Steven Colletti. Anthranilic acid replacements in a niacin receptor agonist. Bioorganic & Medicinal Chemistry Letters 2010, 20 (11) , 3426-3430. https://doi.org/10.1016/j.bmcl.2010.04.001
  41. Fa-Xiang Ding, Hong C. Shen, Larrisa C. Wilsie, Mihajlo L. Krsmanovic, Andrew K. Taggart, Ning Ren, Tian-Quan Cai, Junying Wang, Xinchun Tong, Tom G. Holt, Qing Chen, M. Gerard Waters, Milton L. Hammond, James R. Tata, Steven L. Colletti. Discovery of pyrazolyl propionyl cyclohexenamide derivatives as full agonists for the high affinity niacin receptor GPR109A. Bioorganic & Medicinal Chemistry Letters 2010, 20 (11) , 3372-3375. https://doi.org/10.1016/j.bmcl.2010.04.013
  42. Zixian Chen, Jiangtao Zhu, Haibo Xie, Shan Li, Yongming Wu, Yuefa Gong. Copper(I)-Catalyzed Synthesis of Novel 4-(Trifluoromethyl)-[1,2,3]triazolo[1,5-a]quinoxalines via Cascade Reactions of N-(o-Haloaryl)alkynylimine with Sodium Azide. Advanced Synthesis & Catalysis 2010, 352 (8) , 1296-1300. https://doi.org/10.1002/adsc.200900875
  43. Terry A. Jacobson. A “Hot” Topic in Dyslipidemia Management—“How to Beat a Flush”: Optimizing Niacin Tolerability to Promote Long-term Treatment Adherence and Coronary Disease Prevention. Mayo Clinic Proceedings 2010, 85 (4) , 365-379. https://doi.org/10.4065/mcp.2009.0535
  44. Hong C. Shen, Steven L. Colletti. High-Affinity Niacin Receptor GPR109A Agonists. 2010,,, 72-94. https://doi.org/10.1016/S0065-7743(10)45005-8
  45. David S. Surry, Stephen L. Buchwald. Diamine ligands in copper-catalyzed reactions. Chemical Science 2010, 1 (1) , 13. https://doi.org/10.1039/c0sc00107d

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

This website uses cookies to improve your user experience. By continuing to use the site, you are accepting our use of cookies. Read the ACS privacy policy.

CONTINUE