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 inJournal 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
LanguageEnglish
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
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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.
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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Issue 1
Keywords FLT3
PROTEIN-KINASE
conformational restriction
benzimidazole
KINASE INHIBITORS
ACUTE MYELOID-LEUKEMIA
FMS
Language English
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Snippet A series of 4-arylamido 5-methylisoxazole derivatives incorporating benzimidazole was designed and synthesised by conformational restriction of an in-house...
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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
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