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Bioorg Chem. 2018 Apr;77:429-435. doi: 10.1016/j.bioorg.2018.01.039. Epub 2018 Feb 1.

Structure-based optimization of free fatty acid receptor 1 agonists bearing thiazole scaffold.

Author information

1
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China. Electronic address: lizhengdrug@gdpu.edu.cn.
2
Guangzhou General Pharmaceutical Research Institute Co., Ltd., Guangzhou 510240, PR China.
3
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
4
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: lyzhang@cpu.edu.cn.

Abstract

The free fatty acid receptor 1 (FFA1) plays an important role in amplifying insulin secretion in a glucose dependent manner. We have previously reported a series of FFA1 agonists with thiazole scaffold exemplified by compound 1, and identified a small hydrophobic subpocket partially occupied by the methyl group of compound 1. Herein, we describe further structure optimization to better fit the small hydrophobic subpocket by replacing the small methyl group with other hydrophobic substituents. All of these efforts resulted in the identification of compound 6, a potent FFA1 agonist (EC50 = 39.7 nM) with desired ligand efficiency (0.24) and ligand lipophilicity efficiency (4.7). Moreover, lead compound 6 exhibited a greater potential for decreasing the hyperglycemia levels than compound 1 during an oral glucose tolerance test. In summary, compound 6 is a promising FFA1 agonist for further investigation, and the structure-based study promoted our understanding for the binding pocket of FFA1.

KEYWORDS:

Diabetes; FFA1; Hyperglycemia; Insulin secretion; Ligand efficiency

PMID:
29433092
DOI:
10.1016/j.bioorg.2018.01.039
[Indexed for MEDLINE]

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