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Your search keyword '"Newitt, John A."' showing total 3 results
Start Over Author "Newitt, John A." Topic p38
3 results on '"Newitt, John A."'

1. The identification of novel p38α isoform selective kinase inhibitors having an unprecedented p38α binding mode.

Author

Wrobleski, Stephen T., Lin, Shuqun, Murali Dhar, T.G., Dyckman, Alaric J., Li, Tianle, Pitt, Sidney, Zhang, Rosemary, Fan, Yi, Doweyko, Arthur M., Tokarski, John S., Kish, Kevin F., Kiefer, Susan E., Sack, John S., Newitt, John A., Witmer, Mark R., McKinnon, Murray, Barrish, Joel C., Dodd, John H., Schieven, Gary L., and Leftheris, Katerina

Subjects
*KINASE inhibitors, *MITOGEN-activated protein kinases, *X-ray crystallography, *DRUG design, *TARGETED drug delivery
Abstract

Abstract: A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38β isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed. [Copyright &y& Elsevier]

Published
2013
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2. Utilization of a nitrogen–sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors

Author

Lin, Shuqun, Wrobleski, Stephen T., Hynes, John, Pitt, Sidney, Zhang, Rosemary, Fan, Yi, Doweyko, Arthur M., Kish, Kevin F., Sack, John S., Malley, Mary F., Kiefer, Susan E., Newitt, John A., McKinnon, Murray, Trzaskos, James, Barrish, Joel C., Dodd, John H., Schieven, Gary L., and Leftheris, Katerina

Subjects
*PYRIMIDINES, *MITOGEN-activated protein kinases, *INTERLEUKIN-1, *TUMOR necrosis factors, *ENZYME inhibitors, *NITROGEN compounds, *SULFUR compounds, *MOLECULE-molecule collisions
Abstract

Abstract: The design, synthesis, and structure–activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen–sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38α and provide evidence for the proposed intramolecular nitrogen–sulfur interaction are discussed. [Copyright &y& Elsevier]

Published
2010
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3. The discovery of (R)-2-(sec-butylamino)-N-(2-methyl-5-(methylcarbamoyl)phenyl) thiazole-5-carboxamide (BMS-640994)—A potent and efficacious p38α MAP kinase inhibitor

Author

Hynes, John, Wu, Hong, Pitt, Sidney, Shen, Ding Ren, Zhang, Rosemary, Schieven, Gary L., Gillooly, Kathleen M., Shuster, David J., Taylor, Tracy L., Yang, XiaoXia, McIntyre, Kim W., McKinnon, Murray, Zhang, Hongjian, Marathe, Punit H., Doweyko, Arthur M., Kish, Kevin, Kiefer, Susan E., Sack, John S., Newitt, John A., and Barrish, Joel C.

Subjects
*INFLAMMATION, *PATHOLOGY, *FOCAL adhesion kinase, *PROTEIN-tyrosine kinases
Abstract

Abstract: A novel structural class of p38α MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a potent and selective p38α inhibitor that is orally efficacious in rodent models of acute and chronic inflammation. [Copyright &y& Elsevier]

Published
2008
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