Design of G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) soft drugs with reduced gallbladder-filling effects

  • Eur J Med Chem. 2020 Oct 1;203:112619. doi: 10.1016/j.ejmech.2020.112619.
Fanghui Han  1 ,  Mengmeng Ning  2 ,  Hua Cao  2 ,  Yangliang Ye  2 ,  Ying Feng  2 ,  Ying Leng  3 ,  Jianhua Shen  4
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, No. 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, No. 555 Zu Chong Zhi Road, Shanghai, 201203, China.
  • 3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, No. 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, No. 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address: [email protected].
PMID: 32682201 DOI: 10.1016/j.ejmech.2020.112619
Abstract

The G-protein-coupled bile acid receptor TGR5 agonists were widely developed in type 2 diabetes and gastrointestinal disorders, but were also full of challenges, due to the systemic on-targeted side effects, especially the gallbladder-filling effects. Here, to circumvent these risks, several TGR5 agonists with soft-drug designation had been designed and synthesized with the properties of rapid metabolized after drug effect. Among them, compound 19 showed negligible systemic exposure and favorable gallbladder safety on a 3-day continuous administration, providing a novel strategy for developing TGR5 agonists.

Keywords
Carboxylic ester; GLP-1; Gallbladder-filling effects; Rapid metabolism; Soft drug; TGR5.
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