Design, synthesis of 1,3-dimethylpyrimidine-2,4-diones as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity

Zonghui Ma; Ling Jiang; Guoxin Li; Dailin Liang; Luanfeng Li; Li Liu; Cheng Jiang

doi:10.1016/j.bioorg.2020.103971

Design, synthesis of 1,3-dimethylpyrimidine-2,4-diones as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity

Bioorg Chem. 2020 Aug:101:103971. doi: 10.1016/j.bioorg.2020.103971. Epub 2020 May 25.

Authors

Zonghui Ma¹, Ling Jiang², Guoxin Li¹, Dailin Liang¹, Luanfeng Li³, 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: 32480173
DOI: 10.1016/j.bioorg.2020.103971

Abstract

LDH1A1, one of 19 NAD(P)⁺-dependent aldehyde dehydrogenases, participates in multiple metabolic pathways and has been indicated to play an important role in obesity and diabetes. In this study, a series of 1,3-dimethylpyrimidine-2,4-diones were designed, synthesized and evaluated as novel selective aldehyde dehydrogenase 1A1 inhibitors. Among them, compounds 46, 50, 53, 56 and 57 exhibited excellent inhibitory activity against ALDH1A1 with IC₅₀ values in the low nanomolar range and high selectivity over ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1. Furthermore, in vitro study demonstrated that compound 57 effectively improved glucose consumption in HepG2 cells compared to compound 1 (CM026).

Keywords: ALDH1A1; Enzyme inhibition; Glucose consumption improvement; Selective; Synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aldehyde Dehydrogenase 1 Family / antagonists & inhibitors*
Enzyme Inhibitors
Glucose / metabolism*
Humans
Molecular Structure
Retinal Dehydrogenase / antagonists & inhibitors*
Structure-Activity Relationship

Substances

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