Design, synthesis and biological evaluation of indane derived GPR40 agoPAMs

Barbara Pio; Harry R Chobanian; Yan Guo; Hubert Josien; William K Hagmann; Michael Miller; Maria E Trujillo; Melissa Kirkland; Daniel Kosinski; Joel Mane; Michele Pachanski; Boonlert Cheewatrakoolpong; Eric Ashley; Robert Orr; Michael J Wright; Randal Bugianesi; Sarah Souza; Xiaoping Zhang; Jerry Di Salvo; Adam B Weinglass; Richard Tschirret-Guth; Koppara Samuel; Qing Chen; Jackie Shang; James Lamca; Juliann Ehrhart; Ravi Nargund; Andrew D Howard; Steven L Colletti

doi:10.1016/j.bmcl.2019.04.050

Design, synthesis and biological evaluation of indane derived GPR40 agoPAMs

Bioorg Med Chem Lett. 2019 Jul 15;29(14):1842-1848. doi: 10.1016/j.bmcl.2019.04.050. Epub 2019 May 2.

Authors

Barbara Pio¹, Harry R Chobanian², Yan Guo², Hubert Josien², William K Hagmann², Michael Miller², Maria E Trujillo³, Melissa Kirkland³, Daniel Kosinski³, Joel Mane³, Michele Pachanski³, Boonlert Cheewatrakoolpong³, Eric Ashley⁴, Robert Orr⁴, Michael J Wright⁵, Randal Bugianesi⁵, Sarah Souza⁵, Xiaoping Zhang⁵, Jerry Di Salvo⁵, Adam B Weinglass⁵, Richard Tschirret-Guth⁶, Koppara Samuel⁶, Qing Chen⁶, Jackie Shang⁶, James Lamca⁶, Juliann Ehrhart⁷, Ravi Nargund², Andrew D Howard³, Steven L Colletti²

Affiliations

¹ Discovery Chemistry, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: Barbara.pio@merck.com.
² Discovery Chemistry, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
³ In Vivo Pharmacology, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
⁴ Process Chemistry, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
⁵ In Vitro Pharmacology, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
⁶ Drug Metabolism and Pharmacokinetics, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
⁷ SALAR Discovery, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.

PMID: 31109791
DOI: 10.1016/j.bmcl.2019.04.050

Abstract

GPR40 (FFAR1 or FFA1) is a G protein-coupled receptor, primarily expressed in pancreatic islet β-cells and intestinal enteroendocrine cells. When activated by fatty acids, GPR40 elicits increased insulin secretion from islet β-cells only in the presence of elevated glucose levels. Towards this end, studies were undertaken towards discovering a novel GPR40 Agonist whose mode of action is via Positive Allosteric Modulation of the GPR40 receptor (AgoPAM). Efforts were made to identify a suitable GPR40 AgoPAM tool molecule to investigate mechanism of action and de-risk liver toxicity of GPR40 AgoPAMs due to reactive acyl-glucuronide (AG) metabolites.

Keywords: Diabetes; FFA1; GPCR; GPR40 AgoPAM; Indane.

MeSH terms

Drug Design
Humans
Indans / metabolism*
Receptors, G-Protein-Coupled / agonists*

Substances

Indans
Receptors, G-Protein-Coupled
indan