title: Discovery of diacylphloroglucinols as a new class of GPR40 (FFAR1) agonists.
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%.
authors.affiliation: Department of Medicinal Chemistry, Piramal Life Sciences Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon (E), Mumbai 400063, India.
authors.forename: Sandip B
authors.initials: SB
authors.lastname: Bharate
authors.forename: Atish
authors.initials: A
authors.lastname: Rodge
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Joshi
authors.forename: Jaspreet
authors.initials: J
authors.lastname: Kaur
authors.forename: Shaila
authors.initials: S
authors.lastname: Srinivasan
authors.forename: S Senthil
authors.initials: SS
authors.lastname: Kumar
authors.forename: Asha
authors.initials: A
authors.lastname: Kulkarni-Almeida
authors.forename: Sarala
authors.initials: S
authors.lastname: Balachandran
authors.forename: Arun
authors.initials: A
authors.lastname: Balakrishnan
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D006224:Cricetinae; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D015195:Drug Design; D005227:Fatty Acids / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
chemical_list: C473034:FFAR1 protein, human; D005227:Fatty Acids; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D010696:Phloroglucinol; D002118:Calcium