Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors
DC Field | Value | Language |
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dc.contributor.author | Abdelazem, A.Z. | - |
dc.contributor.author | Al-Sanea, M.M. | - |
dc.contributor.author | Park, B.S. | - |
dc.contributor.author | Park, H.M. | - |
dc.contributor.author | Yoo, K.H. | - |
dc.contributor.author | Sim, T. | - |
dc.contributor.author | Park, J.B. | - |
dc.contributor.author | Lee, S.-H. | - |
dc.contributor.author | Lee, S.H. | - |
dc.date.accessioned | 2021-09-04T23:52:12Z | - |
dc.date.available | 2021-09-04T23:52:12Z | - |
dc.date.created | 2021-06-17 | - |
dc.date.issued | 2015 | - |
dc.identifier.issn | 0223-5234 | - |
dc.identifier.uri | https://scholar.korea.ac.kr/handle/2021.sw.korea/95891 | - |
dc.description.abstract | With the aim of discovering potent and selective kinase inhibitors targeting ROS1 kinase, we designed, synthesized and screened a series of new pyrazol-4-ylpyrimidine derivatives based on our previously discovered lead compound KIST301072. Compounds 6a-e and 7a-e showed good to excellent activities against ROS1 kinase, and seven out of tested compounds were more potent than KIST301072. Compound 7c was the most potent with IC<inf>50</inf> of 24 nM. Moreover, compound 7c showed ROS1 inhibitory selectivity of about 170-fold, relative to that of ALK sharing about 49% amino acid sequence homology with ROS1 kinase in the kinase domain. In silico modeling of 7c at ROS1 active site revealed some essential features for ROS1 inhibitory activity. Based on this study as well as the previous studies, we could build a hypothetical model predicting the required essential features for ROS1 inhibitory activity. The model validity has been tested through a second set of compounds. © 2014 Elsevier Masson SAS. | - |
dc.language | English | - |
dc.language.iso | en | - |
dc.publisher | Elsevier Masson SAS | - |
dc.subject | 2 [3 (3 hydroxy 5 methylphenyl) 4 [6 (isobutylamino) 2 (pyridin 3 yl)pyrimidine 4 yl] 1h pyrazol 1 yl]acetonitrile | - |
dc.subject | 2 [3 (3 hydroxy 5 methylphenyl) 4 [6 [(2 morpholinoethyl)amino] 2 (pyridin 3 yl)pyrimidine 4 yl] 1h pyrazol 1 yl]acetonitrile | - |
dc.subject | 2 [3 (3 hydroxy 5 methylphenyl) 4 [6 [(3 morpholinopropyl)amino] 2 (pyridin 3 yl)pyrimidine 4 yl] 1h pyrazol 1 yl]acetonitrile | - |
dc.subject | 2 [3 (3 hydroxy 5 methylphenyl) 4 [6 [(4 hydroxybutyl)amino] 2 (pyridin 3 yl)pyrimidine 4 yl] 1h pyrazol 1 yl]acetonitrile | - |
dc.subject | 2 [3 (3 methoxy 5 methylphenyl) 4 [6 [(2 morpholinoethyl)amino] 2 (pyridin 3 yl)pyrimidine 4 yl] 1h pyrazol 1 yl]acetonitrile | - |
dc.subject | 2 [3 (3 methoxy 5 methylphenyl) 4 [6 [(3 morpholinopropyl)amino] 2 (pyridin 3 yl)pyrimidine 4 yl] 1h pyrazol 1 yl]acetonitrile | - |
dc.subject | 2 [4 [6 (3 hydroxypropylamino) 2 (pyridin 3 yl)pyrimidin 4 yl] 3 (3 methoxy 5 methylphenyl) 1h pyrazol 1 yl]acetinitrile | - |
dc.subject | 2 [4 [6 (4 hydroxypropylamino) 2 (pyridin 3 yl)pyrimidin 4 yl] 3 (3 methoxy 5 methylphenyl) 1h pyrazol 1 yl]acetinitrile | - |
dc.subject | 2 [4 [6 (isobutylamino) 2 (pyridin 3 yl)pyrimidin 4 yl] 3 (3 methoxy 5 methylphenyl) 1h pyrazol 1 yl]acetinitrile | - |
dc.subject | protein tyrosine kinase inhibitor | - |
dc.subject | pyrazol 4 ylpyrimidine derivative | - |
dc.subject | unclassified drug | - |
dc.subject | protein kinase inhibitor | - |
dc.subject | protein tyrosine kinase | - |
dc.subject | pyrazol-4-ylpyrimidine | - |
dc.subject | pyrazole derivative | - |
dc.subject | pyrimidine derivative | - |
dc.subject | amino acid sequence | - |
dc.subject | Article | - |
dc.subject | biological activity | - |
dc.subject | drug activity | - |
dc.subject | drug design | - |
dc.subject | drug potency | - |
dc.subject | drug screening | - |
dc.subject | drug structure | - |
dc.subject | drug synthesis | - |
dc.subject | enzyme inhibition | - |
dc.subject | IC50 | - |
dc.subject | sequence homology | - |
dc.subject | antagonists and inhibitors | - |
dc.subject | chemical structure | - |
dc.subject | chemistry | - |
dc.subject | dose response | - |
dc.subject | human | - |
dc.subject | metabolism | - |
dc.subject | structure activity relation | - |
dc.subject | synthesis | - |
dc.subject | Dose-Response Relationship, Drug | - |
dc.subject | Humans | - |
dc.subject | Models, Molecular | - |
dc.subject | Molecular Structure | - |
dc.subject | Protein Kinase Inhibitors | - |
dc.subject | Pyrazoles | - |
dc.subject | Pyrimidines | - |
dc.subject | Receptor Protein-Tyrosine Kinases | - |
dc.subject | Structure-Activity Relationship | - |
dc.title | Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Sim, T. | - |
dc.identifier.doi | 10.1016/j.ejmech.2014.11.023 | - |
dc.identifier.scopusid | 2-s2.0-84911399882 | - |
dc.identifier.bibliographicCitation | European Journal of Medicinal Chemistry, v.90, pp.195 - 208 | - |
dc.relation.isPartOf | European Journal of Medicinal Chemistry | - |
dc.citation.title | European Journal of Medicinal Chemistry | - |
dc.citation.volume | 90 | - |
dc.citation.startPage | 195 | - |
dc.citation.endPage | 208 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.subject.keywordPlus | 2 [3 (3 hydroxy 5 methylphenyl) 4 [6 (isobutylamino) 2 (pyridin 3 yl)pyrimidine 4 yl] 1h pyrazol 1 yl]acetonitrile | - |
dc.subject.keywordPlus | 2 [3 (3 hydroxy 5 methylphenyl) 4 [6 [(2 morpholinoethyl)amino] 2 (pyridin 3 yl)pyrimidine 4 yl] 1h pyrazol 1 yl]acetonitrile | - |
dc.subject.keywordPlus | 2 [3 (3 hydroxy 5 methylphenyl) 4 [6 [(3 morpholinopropyl)amino] 2 (pyridin 3 yl)pyrimidine 4 yl] 1h pyrazol 1 yl]acetonitrile | - |
dc.subject.keywordPlus | 2 [3 (3 hydroxy 5 methylphenyl) 4 [6 [(4 hydroxybutyl)amino] 2 (pyridin 3 yl)pyrimidine 4 yl] 1h pyrazol 1 yl]acetonitrile | - |
dc.subject.keywordPlus | 2 [3 (3 methoxy 5 methylphenyl) 4 [6 [(2 morpholinoethyl)amino] 2 (pyridin 3 yl)pyrimidine 4 yl] 1h pyrazol 1 yl]acetonitrile | - |
dc.subject.keywordPlus | 2 [3 (3 methoxy 5 methylphenyl) 4 [6 [(3 morpholinopropyl)amino] 2 (pyridin 3 yl)pyrimidine 4 yl] 1h pyrazol 1 yl]acetonitrile | - |
dc.subject.keywordPlus | 2 [4 [6 (3 hydroxypropylamino) 2 (pyridin 3 yl)pyrimidin 4 yl] 3 (3 methoxy 5 methylphenyl) 1h pyrazol 1 yl]acetinitrile | - |
dc.subject.keywordPlus | 2 [4 [6 (4 hydroxypropylamino) 2 (pyridin 3 yl)pyrimidin 4 yl] 3 (3 methoxy 5 methylphenyl) 1h pyrazol 1 yl]acetinitrile | - |
dc.subject.keywordPlus | 2 [4 [6 (isobutylamino) 2 (pyridin 3 yl)pyrimidin 4 yl] 3 (3 methoxy 5 methylphenyl) 1h pyrazol 1 yl]acetinitrile | - |
dc.subject.keywordPlus | protein tyrosine kinase inhibitor | - |
dc.subject.keywordPlus | pyrazol 4 ylpyrimidine derivative | - |
dc.subject.keywordPlus | unclassified drug | - |
dc.subject.keywordPlus | protein kinase inhibitor | - |
dc.subject.keywordPlus | protein tyrosine kinase | - |
dc.subject.keywordPlus | pyrazol-4-ylpyrimidine | - |
dc.subject.keywordPlus | pyrazole derivative | - |
dc.subject.keywordPlus | pyrimidine derivative | - |
dc.subject.keywordPlus | amino acid sequence | - |
dc.subject.keywordPlus | Article | - |
dc.subject.keywordPlus | biological activity | - |
dc.subject.keywordPlus | drug activity | - |
dc.subject.keywordPlus | drug design | - |
dc.subject.keywordPlus | drug potency | - |
dc.subject.keywordPlus | drug screening | - |
dc.subject.keywordPlus | drug structure | - |
dc.subject.keywordPlus | drug synthesis | - |
dc.subject.keywordPlus | enzyme inhibition | - |
dc.subject.keywordPlus | IC50 | - |
dc.subject.keywordPlus | sequence homology | - |
dc.subject.keywordPlus | antagonists and inhibitors | - |
dc.subject.keywordPlus | chemical structure | - |
dc.subject.keywordPlus | chemistry | - |
dc.subject.keywordPlus | dose response | - |
dc.subject.keywordPlus | human | - |
dc.subject.keywordPlus | metabolism | - |
dc.subject.keywordPlus | structure activity relation | - |
dc.subject.keywordPlus | synthesis | - |
dc.subject.keywordPlus | Dose-Response Relationship, Drug | - |
dc.subject.keywordPlus | Humans | - |
dc.subject.keywordPlus | Models, Molecular | - |
dc.subject.keywordPlus | Molecular Structure | - |
dc.subject.keywordPlus | Protein Kinase Inhibitors | - |
dc.subject.keywordPlus | Pyrazoles | - |
dc.subject.keywordPlus | Pyrimidines | - |
dc.subject.keywordPlus | Receptor Protein-Tyrosine Kinases | - |
dc.subject.keywordPlus | Structure-Activity Relationship | - |
dc.subject.keywordAuthor | Non-small cell lung cancer | - |
dc.subject.keywordAuthor | Pyrazol-4-ylpyrimidine | - |
dc.subject.keywordAuthor | Receptor tyrosine kinase | - |
dc.subject.keywordAuthor | ROS1 kinase inhibitor | - |
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