Discovery of coumarin-based selective aldehyde dehydrogenase 1A1 inhibitors with glucose metabolism improving activity

Dailin Liang; Yazhou Fan; Zhou Yang; Zhenguo Zhang; Meiyang Liu; Li Liu; Cheng Jiang

doi:10.1016/j.ejmech.2019.111923

Discovery of coumarin-based selective aldehyde dehydrogenase 1A1 inhibitors with glucose metabolism improving activity

Eur J Med Chem. 2020 Feb 1:187:111923. doi: 10.1016/j.ejmech.2019.111923. Epub 2019 Dec 3.

Authors

Dailin Liang¹, Yazhou Fan², Zhou Yang¹, Zhenguo Zhang¹, Meiyang Liu³, Li Liu⁴, Cheng Jiang⁵

Affiliations

¹ Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China.
² Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China.
³ Department of Medicinal Chemistry, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China.
⁴ Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China. Electronic address: liulee@cpu.edu.cn.
⁵ Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China. Electronic address: jc@cpu.edu.cn.

PMID: 31816557
DOI: 10.1016/j.ejmech.2019.111923

Abstract

Overexpression of aldehyde dehydrogenase 1A1 (ALDH1A1) is associated with the occurrence and development of obesity and insulin resistance. Herein, a series of coumarin-based ALDH1A1 inhibitors were designed, synthesized and evaluated. Among them, compounds 10, 14 and 26 exhibited potent inhibitory activity against ALDH1A1 and high selectivity over ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1. Optimized compound 10 showed markedly improved pharmacokinetic characters and ADME profiles comparing to the lead compound 1. In vitro study demonstrated that 10 alleviated palmitic acid-induced impairment of glucose consumption in HepG2 cells.

Keywords: ALDH1A1 inhibitors; Coumarin derivatives; Glucose consumption; Synthesis.

MeSH terms

Aldehyde Dehydrogenase 1 Family / antagonists & inhibitors*
Aldehyde Dehydrogenase 1 Family / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Glucose / metabolism*
Hep G2 Cells
Humans
Molecular Structure
Retinal Dehydrogenase / antagonists & inhibitors*
Retinal Dehydrogenase / metabolism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Aldehyde Dehydrogenase 1 Family
ALDH1A1 protein, human
Retinal Dehydrogenase
Glucose