title: Synthesis and biological evaluation of GPR40/FFAR1 agonists containing 3,5-dimethylisoxazole.
abstract: GPR40 is an attractive target due to its glucose-stimulated insulin secretion effect with low risk of causing hypoglycemia, which also can be seen from the clinical studies using TAK-875 (fasiglifam). In the present studies, we discovered a series of analogues containing 3,5-dimethylisoxazole as potent GPR40 agonists, especially compound 11k with an EC50 value of 15.9 nM. Moreover, compound 11k reduced glucose excursion to 23.1% in ICR mice and 29.5% in type 2 diabetic C57BL/6 mice at 30 mg/kg. It also exhibited satisfactory PK profile. Docking studies were conducted to explain the interaction mode of this series. In summary, compound 11k with robust efficacy in vitro and in vivo is a promising drug candidate for further investigation.
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: yanglingyun130@163.com.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Yang
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Lianghui
authors.initials: L
authors.lastname: Si
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Han
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ma
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Junhao
authors.initials: J
authors.lastname: Xing
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Leilei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009 Nanjing, PR China.
authors.forename: Jinpei
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: zhanghb80@163.com.
authors.forename: Huibin
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D010080:Oxazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C473036:Ffar1 protein, mouse; D007004:Hypoglycemic Agents; D010080:Oxazoles; D043562:Receptors, G-Protein-Coupled
keywords: 3,5-Dimethylisoxazole; Diabetes; GPR40 agonist; Oral glucose tolerance test