Conformational restriction of a type II FMS inhibitor leading to discovery of 5-methyl-N-(2-aryl-1H-benzo[d]imidazo-5-yl)isoxazole-4-carboxamide analogues as selective FLT3 inhibitors

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 34; no. 1; pp. 1716 - 1721
• Main Authors: Im, Daseul, Moon, Hyungwoo, Kim, Jingwoong, Oh, Youri, Jang, Miyoung, Hah, Jung-Mi
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 01.01.2019; Taylor & Francis Group
• Subjects: benzimidazole; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biochemistry & Molecular Biology; Chemistry, Medicinal; conformational restriction; Drug Discovery; FLT3; FMS; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - pharmacology; Life Sciences & Biomedicine; Molecular Conformation; Molecular Docking Simulation; Pharmacology & Pharmacy; Protein Binding; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Science & Technology; Short Communication; Structure-Activity Relationship; FLT3; PROTEIN-KINASE; conformational restriction; benzimidazole; KINASE INHIBITORS; ACUTE MYELOID-LEUKEMIA; FMS
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2019.1671837

A series of 4-arylamido 5-methylisoxazole derivatives incorporating benzimidazole was designed and synthesised by conformational restriction of an in-house type II FMS inhibitor. Kinase profiling of one compound revealed interesting features, with increased inhibitory potency towards FLT3 and concomitant loss of potency towards FMS. Several benzimidazole derivatives 5a-5g and 6a-6c containing various hydrophobic moieties were synthesised, and their inhibitory activity against FLT3 was evaluated. Specifically, 5a, 5-methyl-N-(2-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-5-yl) isoxazole-4-carboxamide, exhibited the most potent inhibitory activity against FLT3 (IC 50  = 495 nM), with excellent selectivity profiles.