Discovery of a benzimidazole series as the first highly potent and selective ACSL1 inhibitors
| Autor: | Noriyasu Kondo, Mana Ito, Shuhei Shigaki, Megumi Hato, Ryo Yoshimoto, Takayuki Okuno, Kyohei Hayashi, Naoki Omori, Ayumi Nagasawa |
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| Rok vydání: | 2021 |
| Předmět: |
Benzimidazole
Clinical Biochemistry Pharmaceutical Science 01 natural sciences Biochemistry Mice Structure-Activity Relationship chemistry.chemical_compound Acyl-CoA In vivo Coenzyme A Ligases Drug Discovery Animals Humans Structure–activity relationship Enzyme Inhibitors Molecular Biology Mice Knockout chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry Fatty acid Lipid metabolism 0104 chemical sciences 010404 medicinal & biomolecular chemistry Enzyme chemistry Molecular Medicine Benzimidazoles Selectivity |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 33:127722 |
| ISSN: | 0960-894X |
| Popis: | Long-chain acyl-CoA synthetase-1 (ACSL1), an enzyme that catalyzes the synthesis of long-chain acyl-CoA from the corresponding fatty acids, is believed to play essential roles in lipid metabolism. Structure activity relationship studies based on HTS hit compound 1 delivered the benzimidazole series as the first selective and highly potent ACSL1 inhibitors. Representative compound 13 exhibited not only remarkable inhibitory activity against ACSL1 (IC50 = 0.042 μM) but also excellent selectivity for the other ACSL isoforms. In addition, compound 13 demonstrated an in vivo suppression effect against the production of long-chain acyl-CoAs in mouse. |
| Databáze: | OpenAIRE |
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