Synthesis of heterocyclic ring-fused analogs of HMG499 as novel degraders of HMG-CoA reductase that lower cholesterol.

Cardiovascular Diseases Cholesterol / metabolism Humans Hydroxymethylglutaryl CoA Reductases / genetics Non-alcoholic Fatty Liver Disease Ubiquitination
Cardiovascular disease Cholesterol Degrader HMG-CoA reductase NASH

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
05 Jun 2022
Historique:
received: 07 01 2022
revised: 17 03 2022
accepted: 24 03 2022
pubmed: 10 4 2022
medline: 18 5 2022
entrez: 9 4 2022
Statut: ppublish

Résumé

HMG-CoA reductase (HMGCR) is the rate-limiting enzyme in cholesterol de novo biosynthesis and its degradation may bring therapeutic benefits for the treatment of cardiovascular disease (CVD) and nonalcoholic steatohepatitis (NASH). Before, we disclosed compound HMG499 as a potent HMGCR degrader, which could be a promising agent for treating CVD, however its side-effect of promoting cholesterol accumulation in cells should be eliminated before progression. Herein, a series of novel heterocyclic ring-fused analogs of HMG499 were synthesized and investigated for their activities of stimulating HMGCR degradation using a HMGCR (TM1-8)-GFP reporting system. Among them, the most active compound 29 (QH536) showed an EC

Identifiants

DOI: 10.1016/j.ejmech.2022.114323 PMID: 35397399
pubmed: 35397399
pii: S0223-5234(22)00225-2
doi: 10.1016/j.ejmech.2022.114323
pii:
doi:

Substances chimiques

Cholesterol 97C5T2UQ7J
Hydroxymethylglutaryl CoA Reductases EC 1.1.1.-

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

114323

Informations de copyright

Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Auteurs

Xing-Zi Li (XZ)

Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.

Shi-You Jiang (SY)

Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Institute for Advanced Studies, Wuhan University, 430072, Wuhan, China.

Guo-Qiang Li (GQ)

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.

Qian-Ru Jiang (QR)

Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.

Jue-Wan Li (JW)

School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.

Chen-Chen Li (CC)

Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.

Yu-Qin Han (YQ)

Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Institute for Advanced Studies, Wuhan University, 430072, Wuhan, China.

Bao-Liang Song (BL)

Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Institute for Advanced Studies, Wuhan University, 430072, Wuhan, China.

Xin-Ran Ma (XR)

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China. Electronic address: xrma@bio.ecnu.edu.cn.

Wei Qi (W)

School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. Electronic address: qiwei@shanghaitech.edu.cn.

Wen-Wei Qiu (WW)

Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China. Electronic address: wwqiu@chem.ecnu.edu.cn.

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Classifications MeSH

questionsmedicales.fr › Maladies cardiovasculaires › Synthesis of heterocyclic ring-fused analogs...
questionsmedicales.fr › Lipides › Lipides membranaires › Stérols › Cholestérol › Synthesis of heterocyclic ring-fused analogs...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Synthesis of heterocyclic ring-fused analogs...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Alcohol oxidoreductases › NAD (+) and NADP (+) dependent Alcohol oxidoreductases › 3-Hydroxyacyl-CoA dehydrogenases › Hydroxymethylglutaryl-CoA reductases › Synthesis of heterocyclic ring-fused analogs...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Stéatose hépatique › Stéatose hépatique non alcoolique › Synthesis of heterocyclic ring-fused analogs...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Modification traductionnelle des protéines › Maturation post-traductionnelle des protéines › Ubiquitination › Synthesis of heterocyclic ring-fused analogs...