Discovery of HWL-088: A highly potent FFA1/GPR40 agonist bearing a phenoxyacetic acid scaffold

  • Bioorg Chem. 2019 Nov;92:103209. doi: 10.1016/j.bioorg.2019.103209.
Zheng Li  1 ,  Qiang Ren  1 ,  Xuekun Wang  2 ,  Zongtao Zhou  1 ,  Lijun Hu  1 ,  Liming Deng  1 ,  Li Guan  3 ,  Qianqian Qiu  4
Affiliations
  • 1. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
  • 2. College of Pharmacy, Liaocheng University, Liaocheng 252059, PR China.
  • 3. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China. Electronic address: [email protected].
  • 4. School of Pharmacy, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, Yancheng Teachers' University, Yancheng, PR China. Electronic address: [email protected].
PMID: 31487621 DOI: 10.1016/j.bioorg.2019.103209
Abstract

Based on a previously reported phenoxyacetic acid scaffold, compound 7 (HWL-088) has been identified as a superior Free Fatty Acid Receptor 1 (FFA1) agonist by comprehensive structure-activity relationship study. Our results indicated that the introduction of ortho-fluoro greatly increased the activity of phenoxyacetic acid series, and the unique structure-activity relationship in biphenyl moiety is different from previously reported FFA1 agonists. Moreover, the modeling study was also performed to better understand the binding mode of present series. Compound 7 significantly improved glucose tolerance both in normal and diabetic models, and even exerted greater potential on glucose control than that of TAK-875. These findings provided a novel candidate HWL-088, which is currently in preclinical study to evaluate its potential for the treatment of diabetes.

Keywords
Diabetes; FFA1; GPR40; Hyperglycemia; Phenoxyacetic acid.
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