Synthesis and biological evaluation of GPR40/FFAR1 agonists containing 3,5-dimethylisoxazole

Eur J Med Chem. 2016 Jun 30:116:46-58. doi: 10.1016/j.ejmech.2016.03.054.

Lingyun Yang ¹, Jian Zhang ², Lianghui Si ², Li Han ², Bo Zhang ², Hui Ma ², Junhao Xing ², Leilei Zhao ², Jinpei Zhou ³, Huibin Zhang ⁴

Affiliations

1 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: yanglingyun130@163.com.
2 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
3 Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009 Nanjing, PR China.
4 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.

PMID: 27054485 DOI: 10.1016/j.ejmech.2016.03.054

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.

Keywords

3,5-Dimethylisoxazole; Diabetes; GPR40 agonist; Oral glucose tolerance test.

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