Identification of triazolopyridazinones as potent p38α inhibitors (original) (raw)
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Continued exploration of the triazolopyridine scaffold as a platform for p38 MAP kinase inhibition
Bioorganic & Medicinal Chemistry Letters, 2010
The structure based drug design, synthesis and structure-activity relationship of a series of C6 sulfur linked triazolopyridine based p38 inhibitors are described. The metabolic deficiencies of this series were overcome through changes in the C6 linker from sulfur to methylene, which was predicted by molecular modeling to be bioisosteric. X-ray of the ethylene linked compound 61 confirmed the predicted binding orientation of the scaffold in the p38 enzyme.
p38 MAP kinase inhibitors. Part 6: 2-Arylpyridazin-3-ones as templates for inhibitor design
Bioorganic & Medicinal Chemistry Letters, 2006
p38 inhibitors based on 3,4-dihydropyrido [4,3-d]pyrimidazin-2-one template were synthesized and their SAR explored. Benchmark compounds 30, 35, and 36 were found to be potent against the enzyme. Crystal structure of p38 in complex with 30 indicated a key p-stacking interaction with the pendant tyrosine residue-35 in the glycine-rich loop.
Bioorganic & Medicinal Chemistry Letters, 2011
A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the substitution pattern on the N-phenyl ring. Further optimization produced the highly selective and potent pyridinones 2 and 3. These inhibitors exhibited activity in both acute and chronic models of inflammation.
Chemical biology & drug design, 2015
The identification, synthesis, biological activity and binding mode prediction of a series of pyrazolobenzothiazines as novel p38α MAPK inhibitors are reported. Some of these compounds showed interesting activity in both p38α MAPK and TNF-α release assays. Derivative 6 emerged as the most interesting compound with IC50 (p38α) = 0.457 μM, IC50 (TNF-α) = 0.5 μM and a promising kinase selectivity profile. The obtained results strongly indicate the pyrazolobenzothiazine core as a new p38α inhibitor chemotype worthy of future chemical optimization efforts directed toward identifying a new generation of anti-inflammatory agents. This article is protected by copyright. All rights reserved.
Journal of Medicinal Chemistry, 2010
The p38 mitogen-activated protein kinase (MAPK) plays an important role in the production of proinflammatory cytokines, making it an attractive target for the treatment of various inflammatory diseases. A series of pyridazinopyridinone compounds were designed as novel p38 kinase inhibitors. A structure-activity investigation identified several compounds possessing excellent potency in both enzyme and human whole blood assays. Among them, compound 31 exhibited good pharmacokinetic properties and showed excellent selectivity against other related kinases. In addition, 31 demonstrated efficacy in a collagen-induced arthritis disease model in rats.
Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase
Bioorganic & medicinal …, 2009
The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38a. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation.