title: Discovery of Potent and Orally Bioavailable GPR40 Full Agonists Bearing Thiophen-2-ylpropanoic Acid Scaffold.
abstract: The free fatty acid receptor GPR40 is predominantly expressed in pancreatic β-cells and enhances insulin secretion in a glucose dependent manner. Therefore, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia for the treatment of type 2 diabetes mellitus (T2DM). Chemically and structurally diverse GPR40 agonists with high safety are pursued for the clinical development of GPR40-based pharmacotherapeutics. Herein we report our design and discovery of a new chemotype of GPR40 agonists free of the typical phenylpropanoic acid scaffold. The thiophen-2-ylpropanoic acid containing GPR40 modulators functioned as full agonists with high-efficacy response (Emax) and reduced lipophilicity. Significantly, the lead compound in this series, (R)-7k, exhibited more potent in vitro glucose-stimulated insulin secretion and in vivo glucose-lowering effects (10 mg/kg, po) than the GPR40 partial agonist TAK-875, which was once in phase III clinical trials, and high selectivity over the relevant receptors GPR120 and PPARγ.
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences , Beijing 100049, China.
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences , Beijing 100049, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Huang
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|Department of Chemistry, Shanghai University , 99 Shangda Road, Shanghai 200444, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Chemistry, Shanghai University , 99 Shangda Road, Shanghai 200444, China.
authors.forename: Bin
authors.identifier: 0000-0002-9251-6930
authors.initials: B
authors.lastname: Xu
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: He-Yao
authors.initials: HY
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Ya-Qiu
authors.identifier: 0000-0002-9209-0503
authors.initials: YQ
authors.lastname: Long
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D008297:Male; D008813:Mice, Inbred ICR; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D013876:Thiophenes / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D001572:Benzofurans; D001786:Blood Glucose; C473034:FFAR1 protein, human; D007004:Hypoglycemic Agents; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C557331:TAK-875; D013876:Thiophenes