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
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 concom...
Saved in:
Published in | Journal of enzyme inhibition and medicinal chemistry Vol. 34; no. 1; pp. 1716 - 1721 |
---|---|
Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
ABINGDON
Taylor & Francis
01.01.2019
Taylor & Francis Group |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Supplemental data for this article can be accessed here. |
ISSN: | 1475-6366 1475-6374 |
DOI: | 10.1080/14756366.2019.1671837 |