Synthesis and structure-activity relationship of dihydrobenzofuran derivatives as novel human GPR119 agonists

Xiang-Yang Ye; Christian L Morales; Ying Wang; Karen A Rossi; Sarah E Malmstrom; Mojgan Abousleiman; Larisa Sereda; Atsu Apedo; Jeffrey A Robl; Keith J Miller; John Krupinski; Dean A Wacker

doi:10.1016/j.bmcl.2014.03.096

Synthesis and structure-activity relationship of dihydrobenzofuran derivatives as novel human GPR119 agonists

Bioorg Med Chem Lett. 2014 Jun 1;24(11):2539-45. doi: 10.1016/j.bmcl.2014.03.096. Epub 2014 Apr 8.

Authors

Affiliations

¹ Department of Chemistry, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States. Electronic address: xiang-yang.ye@bms.com.
² Department of Chemistry, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.
³ CADD, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.
⁴ Leads Discovery and Optimization, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.
⁵ Department of Biology, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.
⁶ Bioanalytical and Discovery Analytical Sciences, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.

PMID: 24755425
DOI: 10.1016/j.bmcl.2014.03.096

Abstract

Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R(1) attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R(2). The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles.

Keywords: Agonist; GPR119; Type 2 diabetes.

MeSH terms

Benzofurans / chemical synthesis
Benzofurans / chemistry
Benzofurans / pharmacology*
Cell Line
Dose-Response Relationship, Drug
Humans
Models, Molecular
Molecular Structure
Receptors, G-Protein-Coupled / agonists*
Structure-Activity Relationship

Substances

Benzofurans
GPR119 protein, human
Receptors, G-Protein-Coupled