2. Academic Validation
  3. Design, synthesis and biological evaluation of indane derived GPR40 agoPAMs

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.
Barbara Pio 1,  Harry R Chobanian 2,  Yan Guo 2,  Hubert Josien 2,  William K Hagmann 2,  Michael Miller 2,  Maria E Trujillo 3,  Melissa Kirkland 3,  Daniel Kosinski 3,  Joel Mane 3,  Michele Pachanski 3,  Boonlert Cheewatrakoolpong 3,  Eric Ashley 4,  Robert Orr 4,  Michael J Wright 5,  Randal Bugianesi 5,  Sarah Souza 5,  Xiaoping Zhang 5,  Jerry Di Salvo 5,  Adam B Weinglass 5,  Richard Tschirret-Guth 6,  Koppara Samuel 6,  Qing Chen 6,  Jackie Shang 6,  James Lamca 6,  Juliann Ehrhart 7,  Ravi Nargund 2,  Andrew D Howard 3,  Steven L Colletti 2
Affiliations

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.

Figures