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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Published in | Journal of enzyme inhibition and medicinal chemistry Vol. 34; no. 1; pp. 1716 - 1721 |
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Main Authors | , , , , , |
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Abstract | 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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AbstractList | 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
and
containing various hydrophobic moieties were synthesised, and their inhibitory activity against FLT3 was evaluated. Specifically,
, 5-methyl-
-(2-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-1
-benzo[d]imidazole-5-yl) isoxazole-4-carboxamide, exhibited the most potent inhibitory activity against FLT3 (IC
= 495 nM), with excellent selectivity profiles. 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)-1 H -benzo[d]imidazole-5-yl) isoxazole-4-carboxamide, exhibited the most potent inhibitory activity against FLT3 (IC 50 = 495 nM), with excellent selectivity profiles. 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. 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 (IC50?= 495?nM), with excellent selectivity profiles. 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 (IC50 = 495 nM), with excellent selectivity profiles. |
Author | Kim, Jingwoong Oh, Youri Im, Daseul Jang, Miyoung Hah, Jung-Mi Moon, Hyungwoo |
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Cites_doi | 10.1007/s10637-017-0470-z 10.1016/j.ccr.2007.04.021 10.1158/1535-7163.MCT-16-0876 10.1016/S1470-2045(17)30416-3 10.4155/FMC.14.50 10.1158/2159-8290.CD-15-0060 10.1038/leu.2012.114 10.1021/cr000225s 10.1016/j.ejmech.2015.08.031 10.1021/jm060199b 10.1158/2159-8290.CD-13-0070 10.1182/blood-2002-02-0492 10.1016/j.tips.2014.09.007 10.1021/jm201710f 10.1016/j.phrs.2015.10.021 10.1002/jlb.64.3.409 10.1084/jem.192.5.719 10.1096/fasebj.9.9.7601337 10.1016/S0960-894X(99)00668-X 10.2174/138955706775197839 10.4155/fmc.14.50 |
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Keywords | FLT3 PROTEIN-KINASE conformational restriction benzimidazole KINASE INHIBITORS ACUTE MYELOID-LEUKEMIA FMS |
Language | English |
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SubjectTerms | 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 |
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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 |
URI | https://www.tandfonline.com/doi/abs/10.1080/14756366.2019.1671837 http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestApp=WOS&DestLinkType=FullRecord&UT=000488464600001 https://www.ncbi.nlm.nih.gov/pubmed/31571509 https://search.proquest.com/docview/2299772744 https://pubmed.ncbi.nlm.nih.gov/PMC6781469 https://doaj.org/article/6209deee62bc403299eb06ef984dbde7 |
Volume | 34 |
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