OpenLB
Open Library of Bioscience
Advanced Search
ACS medicinal chemistry letters
Mar 12, 2015;6 (3): 266-70.

Discovery of DS-1558: A Potent and Orally Bioavailable GPR40 Agonist.

Rieko Takano, Masao Yoshida, Masahiro Inoue, Takeshi Honda, Ryutaro Nakashima, Koji Matsumoto, Tatsuya Yano, Tsuneaki Ogata, Nobuaki Watanabe, Masakazu Hirouchi, Tomoko Yoneyama, Shuichiro Ito, Narihiro Toda
Author Information
  1. Rieko Takano: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  2. Masao Yoshida: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  3. Masahiro Inoue: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  4. Takeshi Honda: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  5. Ryutaro Nakashima: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  6. Koji Matsumoto: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  7. Tatsuya Yano: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  8. Tsuneaki Ogata: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  9. Nobuaki Watanabe: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  10. Masakazu Hirouchi: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  11. Tomoko Yoneyama: Drug Discovery and Biomedical Technology Unit, Daiichi Sankyo RD Novare Co., Ltd. , 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
  12. Shuichiro Ito: Drug Discovery and Biomedical Technology Unit, Daiichi Sankyo RD Novare Co., Ltd. , 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
  13. Narihiro Toda: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 25815144 DOI: 10.1021/ml500391n

Abstract

GPR40 is a G protein-coupled receptor that is predominantly expressed in pancreatic β-cells. GPR40 agonists stimulate insulin secretion in the presence of high glucose concentration. On the basis of this mechanism, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia. The improvement of in vitro activity and metabolic stability of compound 1 led to the discovery of 13, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid, as a potent and orally available GPR40 agonist. Compound 13 (DS-1558) was found to have potent glucose lowering effects during an oral glucose tolerance test in ZDF rats.

Keywords

GPR40 agonist diabetes glucose lowering insulin secretagogue

References

  1. Biochem Biophys Res Commun. 2005 Sep 16;335(1):97-104 [PMID: 16081037]
  2. Curr Med Chem. 2008;15(1):61-74 [PMID: 18220763]
  3. Bioorg Med Chem Lett. 2010 Feb 1;20(3):1298-301 [PMID: 20064714]
  4. Drugs. 2004;64(12):1339-58 [PMID: 15200348]
  5. Lancet. 2011 Jul 2;378(9785):31-40 [PMID: 21705069]
  6. J Clin Endocrinol Metab. 2005 Jan;90(1):501-6 [PMID: 15483097]
  7. Diabetes. 2008 Aug;57(8):2211-9 [PMID: 18477808]
  8. Biochem Biophys Res Commun. 2003 Feb 7;301(2):406-10 [PMID: 12565875]
  9. Lancet. 2012 Apr 14;379(9824):1403-11 [PMID: 22374408]
  10. Eur J Pharmacol. 2014 Aug 15;737:194-201 [PMID: 24858371]
  11. Bioorg Med Chem Lett. 2014 Jul 1;24(13):2949-53 [PMID: 24835985]
  12. J Biol Chem. 2003 Mar 28;278(13):11303-11 [PMID: 12496284]
  13. J Diabetes Complications. 2005 Jan-Feb;19(1):60-4 [PMID: 15642492]
  14. Expert Opin Investig Drugs. 2012 Mar;21(3):321-8 [PMID: 22292451]
  15. Bioorg Med Chem Lett. 2012 Jan 15;22(2):1267-70 [PMID: 22217876]
  16. Bioorg Med Chem Lett. 2007 Mar 15;17 (6):1584-9 [PMID: 17240142]
  17. Front Endocrinol (Lausanne). 2012 Jan 03;2:112 [PMID: 22649399]
  18. Curr Med Res Opin. 2010 May;26(5):1013-22 [PMID: 20199137]
  19. ACS Med Chem Lett. 2013 Jun 17;4(8):790-4 [PMID: 24900747]
  20. ACS Med Chem Lett. 2013 May 9;4(5):441-445 [PMID: 23687558]
  21. Am J Physiol Endocrinol Metab. 2005 Oct;289(4):E670-7 [PMID: 15914509]
  22. ACS Med Chem Lett. 2012 Aug 15;3(9):726-30 [PMID: 24900539]
  23. J Pharmacol Exp Ther. 2011 Oct;339(1):228-37 [PMID: 21752941]
  24. Expert Opin Ther Pat. 2009 Feb;19(2):237-64 [PMID: 19441920]
  25. Nature. 2003 Mar 13;422(6928):173-6 [PMID: 12629551]
  26. ACS Med Chem Lett. 2010 Jun 18;1(6):290-4 [PMID: 24900210]
  27. ACS Med Chem Lett. 2010 Jul 02;1(7):345-9 [PMID: 24900217]
  28. Pharmacol Rev. 2003 Mar;55(1):105-31 [PMID: 12615955]
Journal Article

Word Cloud

Created with Highcharts 10.0.0GPR40glucoseinsulinagonists13potentagonistloweringGprotein-coupledreceptorpredominantlyexpressedpancreaticβ-cellsstimulatesecretionpresencehighconcentrationbasismechanismpossiblenovelsecretagoguesreducedriskhypoglycemiaimprovementvitroactivitymetabolicstabilitycompound1leddiscovery3S-3-ethoxy-3-4-{[1R-4-trifluoromethyl-23-dihydro-1H-inden-1-yl]oxy}phenylpropanoicacidorallyavailableCompoundDS-1558foundeffectsoraltolerancetestZDFratsDiscoveryDS-1558:PotentOrallyBioavailableAgonistdiabetessecretagogue

Similar Articles

Cited By