2018年3月30日金曜日

GPR40 OPTIMIZATION 2018 for Diabetics 2018

Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists

 
Research and Development, Bristol-Myers Squibb Co., P.O. Box 4000, Princeton, New Jersey 08540-4000, United States
J. Med. Chem., 2018, 61 (3), pp 681–694
DOI: 10.1021/acs.jmedchem.7b00982
Publication Date (Web): January 9, 2018
Copyright © 2018 American Chemical Society
*Phone: +1-609-466-5075. E-mail: jun.shi@bms.com.

Abstract

Abstract Image
 
 
 
G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion.
 
 
Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion.
 
 
Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.
 
 
 
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b00982. Full crystallographic data for compound 8 have been deposited to the Cambridge Crystallographic Data Center (CCDC reference no. 1559162) and can be obtained free of charge via the Internet at http://www.ccdc.cam.ac.uk.
  • Experimental procedures for the synthesis of compounds 3b35 and methods for in vitro and in vivo biological studies (PDF)
  • X-ray crystallographic data for 8 (CIF)
  • Molecular formula strings (CSV)




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Article Views: 1,653 Times
Received 5 July 2017
Published online 9 January 2018
Published in print 8 February 2018
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1 件のコメント:

  1. Some Sort of Rhodanines might be promissing for further OPTIMIZATION !!

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