Discovery of a benzimidazole series as the first highly potent and selective ACSL1 inhibitors
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Kyohei Hayashi1, Noriyasu Kondo1, Naoki Omori1
1Pharmaceutical Research Division, Shionogi Pharmaceutical Research Center, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
Abstract:
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.
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