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...

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Autores principales: Im, Daseul, Moon, Hyungwoo, Kim, Jingwoong, Oh, Youri, Jang, Miyoung, Hah, Jung-Mi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2019
Materias:
Short Communication
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781469/
https://www.ncbi.nlm.nih.gov/pubmed/31571509
http://dx.doi.org/10.1080/14756366.2019.1671837
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author Im, Daseul
Moon, Hyungwoo
Kim, Jingwoong
Oh, Youri
Jang, Miyoung
Hah, Jung-Mi
author_facet Im, Daseul
Moon, Hyungwoo
Kim, Jingwoong
Oh, Youri
Jang, Miyoung
Hah, Jung-Mi
author_sort Im, Daseul
collection PubMed
description 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.
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spelling pubmed-67814692019-10-18 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 Im, Daseul Moon, Hyungwoo Kim, Jingwoong Oh, Youri Jang, Miyoung Hah, Jung-Mi J Enzyme Inhib Med Chem Short Communication 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. Taylor & Francis 2019-10-01 /pmc/articles/PMC6781469/ /pubmed/31571509 http://dx.doi.org/10.1080/14756366.2019.1671837 Text en © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Short Communication
Im, Daseul
Moon, Hyungwoo
Kim, Jingwoong
Oh, Youri
Jang, Miyoung
Hah, Jung-Mi
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781469/
https://www.ncbi.nlm.nih.gov/pubmed/31571509
http://dx.doi.org/10.1080/14756366.2019.1671837
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