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 3b–35 and methods for in vitro and in vivo biological studies (PDF)
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†Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Chemical Biology Innovation Laboratory, College of Chemistry and Materials Science, Northwest University, Xi’an710127, P. R. China
‡Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, 309 East Second Street, Pomona, California91766, United States
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Learn more about these metrics Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.
The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.
