DC Field | Value | Language |
---|---|---|
dc.contributor.author | C H Jin | - |
dc.contributor.author | M Krishnaiah | - |
dc.contributor.author | D Sreenu | - |
dc.contributor.author | V B Subrahmanyam | - |
dc.contributor.author | K S Rao | - |
dc.contributor.author | H J Lee | - |
dc.contributor.author | S J Park | - |
dc.contributor.author | H J Park | - |
dc.contributor.author | Kiho Lee | - |
dc.contributor.author | Y Y Sheen | - |
dc.contributor.author | D K Kim | - |
dc.date.accessioned | 2017-04-19T09:54:00Z | - |
dc.date.available | 2017-04-19T09:54:00Z | - |
dc.date.issued | 2014 | - |
dc.identifier.issn | 0022-2623 | - |
dc.identifier.uri | 10.1021/jm500115w | ko |
dc.identifier.uri | https://oak.kribb.re.kr/handle/201005/12020 | - |
dc.description.abstract | A series of 2-substituted-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6- methylpyridin-2-yl)imidazoles was synthesized and evaluated to optimize a prototype inhibitor of TGF-β type I receptor kinase (ALK5), 6. Combination of replacement of a quinoxalin-6-yl moiety of 6 with a [1,2,4]triazolo[1,5-a] pyridin-6-yl moiety, insertion of a methyleneamino linker, and a o-F substituent in the phenyl ring markedly increased ALK5 inhibitory activity, kinase selectivity, and oral bioavailability. The 12b (EW-7197) inhibited ALK5 with IC50 value of 0.013 μM in a kinase assay and with IC50 values of 0.0165 and 0.0121 μM in HaCaT (3TP-luc) stable cells and 4T1 (3TP-luc) stable cells, respectively, in a luciferase assay. Selectivity profiling of 12b using a panel of 320 protein kinases revealed that it is a highly selective ALK5/ALK4 inhibitor. Pharmacokinetic study with 12b·HCl in rats showed an oral bioavailability of 51% with high systemic exposure (AUC) of 1426 ng × h/mL and maximum plasma concentration (Cmax) of 1620 ng/mL. Rational optimization of 6 has led to the identification of a highly potent, selective, and orally bioavailable ALK5 inhibitor 12b. | - |
dc.publisher | Amer Chem Soc | - |
dc.title | Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic | - |
dc.title.alternative | Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic | - |
dc.type | Article | - |
dc.citation.title | Journal of Medicinal Chemistry | - |
dc.citation.number | 10 | - |
dc.citation.endPage | 4238 | - |
dc.citation.startPage | 4213 | - |
dc.citation.volume | 57 | - |
dc.contributor.affiliatedAuthor | Kiho Lee | - |
dc.contributor.alternativeName | Jin | - |
dc.contributor.alternativeName | Krishnaiah | - |
dc.contributor.alternativeName | Sreenu | - |
dc.contributor.alternativeName | Subrahmanyam | - |
dc.contributor.alternativeName | Rao | - |
dc.contributor.alternativeName | 이화정 | - |
dc.contributor.alternativeName | 박소정 | - |
dc.contributor.alternativeName | 박현주 | - |
dc.contributor.alternativeName | 이기호 | - |
dc.contributor.alternativeName | Sheen | - |
dc.contributor.alternativeName | 김대기 | - |
dc.identifier.bibliographicCitation | Journal of Medicinal Chemistry, vol. 57, no. 10, pp. 4213-4238 | - |
dc.identifier.doi | 10.1021/jm500115w | - |
dc.description.journalClass | Y | - |
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