The discovery of VX-745: A novel and selective p38α kinase inhibitor

ACS Medicinal Chemistry Letters

Volumn 2, Issue 10, 2011, Pages 758-763

  Duffy, John P ^a   Harrington, Edmund M ^b   Salituro, Francesco G ^c   Cochran, John E ^a   Green, Jeremy ^a   Gao, Huai ^a   Bemis, Guy W ^a   Evindar, Ghotas ^d   Galullo, Vincent P ^e   Ford, Pamella J ^a   Germann, Ursula A ^a   Wilson, Keith P ^f   Bellon, Steven F ^g   Chen, Guanging ^b   Taslimi, Paul ^b   Jones, Peter ^a   Huang, Cassey ^a   Pazhanisamy, S ^a   Wang, Yow Ming ^h   Murcko, Mark A ^a   Su, Michael S S ^c   more..

^a VERTEX PHARMACEUTICALS   (United States)

^b NOVARTIS   (United States)

^c AGIOS PHARMACEUTICALS   (United States)

^d GLAXOSMITHKLINE   (United States)

^e ASTRAZENECA   (United Kingdom)

^f Takeda San Diego Inc   (United States)

^g Department of Structural Biology   (United States)

^h AMGEN INC   (United States)

Author keywords

inflammatory diseases; p38 inhibitor; VX 745

Indexed keywords

4 (4 FLUOROPHENYL) 2 (4 METHYLSULFINYLPHENYL) 5 (4 PYRIDYL)IMIDAZOLE; 5 (2,6 DICHLOROPHENYL) 2 (2,4 DIFLUOROPHENYLTHIO)PYRIMIDO[1,6 B]PYRIDAZIN 6 ONE; INTERLEUKIN 1BETA; TUMOR NECROSIS FACTOR ALPHA;

ARTICLE; CYTOKINE RELEASE; DOG; DRUG ABSORPTION; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG IDENTIFICATION; DRUG SCREENING; DRUG SELECTIVITY; DRUG SYNTHESIS; ENZYME ACTIVITY; FEMALE; IN VIVO STUDY; INFLAMMATION; MASS SPECTROMETRY; MOUSE; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PRIORITY JOURNAL; SINGLE DRUG DOSE; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

EID: 80054752044     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml2001455     Document Type: Article

References (28)

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22. 2, 25 mM NaCl, 1 mM DTT, 20 μg/mL BSA, and 1.5% DMSO. Final substrate concentrations in the assay were 100 μM ATP and 200 μM peptide (KRELVEPLTPSGEAPNQALLR). Assays were carried out at 30 °C using 15 nM p38. The final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 200 μM NADH, 140 μg/mL pyruvate kinase, and 10 μg/mL lactate dehydrogenase.
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28. Compound 3 (VX-745) attained clinical proof-of-principle correlating inhibition of p38 with anti-inflammatory effect, but clinical development was suspended following adverse effects findings in non-clinical studies. http://www.prnewswire.com/news-releases/vertex-moves-to-re-allocate-resources- from-vx-745-in-p38-map-kinase-program-to-accelerate-development-of-second- generation-drug-candidates-vx-702-and-vx-850-72104487.html.