Discovery of diacylphloroglucinols as a new class of GPR40 (FFAR1) agonists

Sandip B Bharate; Atish Rodge; Rajendra K Joshi; Jaspreet Kaur; Shaila Srinivasan; S Senthil Kumar; Asha Kulkarni-Almeida; Sarala Balachandran; Arun Balakrishnan; Ram A Vishwakarma

doi:10.1016/j.bmcl.2008.10.085

Discovery of diacylphloroglucinols as a new class of GPR40 (FFAR1) agonists

Bioorg Med Chem Lett. 2008 Dec 15;18(24):6357-61. doi: 10.1016/j.bmcl.2008.10.085. Epub 2008 Nov 1.

Authors

Sandip B Bharate¹, Atish Rodge, Rajendra K Joshi, Jaspreet Kaur, Shaila Srinivasan, S Senthil Kumar, Asha Kulkarni-Almeida, Sarala Balachandran, Arun Balakrishnan, Ram A Vishwakarma

Affiliation

¹ Department of Medicinal Chemistry, Piramal Life Sciences Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon (E), Mumbai 400063, India.

PMID: 18993064
DOI: 10.1016/j.bmcl.2008.10.085

Abstract

In this letter, we report discovery of diacylphloroglucinol compounds as a new class of GPR40 (FFAR1) agonists. Several diacylphloroglucinols with varying length of acyl functionality and substitution on aromatic hydroxyls were synthesized and evaluated for GPR40 agonism using functional calcium-flux assay. Out of 17 compounds evaluated, 14, 17, 19 and 25 exhibited good GPR40 agonistic activity with EC(50) values ranging from 0.07 to 8 microM (pEC(50) 7.12-5.09), respectively, with maximal agonistic response of 84-102%.

MeSH terms

Animals
CHO Cells
Calcium / chemistry
Chemistry, Pharmaceutical / methods*
Cricetinae
Cricetulus
Diabetes Mellitus, Type 2 / drug therapy*
Drug Design
Fatty Acids / chemistry
Humans
Ligands
Models, Chemical
Phloroglucinol / analogs & derivatives*
Phloroglucinol / chemical synthesis
Phloroglucinol / pharmacology*
Rats
Receptors, G-Protein-Coupled / agonists*

Substances

FFAR1 protein, human
Fatty Acids
Ligands
Receptors, G-Protein-Coupled
Phloroglucinol
Calcium