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Literature DB >> 15801819

Design of potent and selective 2-aminobenzimidazole-based p38alpha MAP kinase inhibitors with excellent in vivo efficacy.

Alfonso de Dios¹, Chuan Shih, Beatriz López de Uralde, Concepción Sánchez, Miriam del Prado, Luisa M Martín Cabrejas, Sehila Pleite, Jaime Blanco-Urgoiti, María José Lorite, C Richard Nevill, Rosanne Bonjouklian, Jeremy York, Michal Vieth, Yong Wang, Nicholas Magnus, Robert M Campbell, Bryan D Anderson, Denis J McCann, Deborah D Giera, Paul A Lee, Richard M Schultz, Li C Li, Lea M Johnson, Jeffrey A Wolos.

Abstract

We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38alphainhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNFalpha release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other p38 reference compounds. A SAR strategy to address CyP3A4 liability is also described.

Entities: Chemical Disease Gene Species

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Year: 2005 PMID： 15801819 DOI： 10.1021/jm048978k

Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446

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Cited

7 in total

1. p38 mitogen-activated protein kinase promotes cell survival in response to DNA damage but is not required for the G(2) DNA damage checkpoint in human cancer cells.

Authors: Mark S Phong; Robert D Van Horn; Shuyu Li; Gregory Tucker-Kellogg; Uttam Surana; Xiang S Ye
Journal: Mol Cell Biol Date: 2010-06-01 Impact factor: 4.272

Review 2. Interleukins in glioblastoma pathophysiology: implications for therapy.

Authors: Y T Yeung; K L McDonald; T Grewal; L Munoz
Journal: Br J Pharmacol Date: 2013-02 Impact factor: 8.739

3. Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein-protein interaction profile.

Authors: Jeffrey N Miner; Bob Ardecky; Khalid Benbatoul; Kimberly Griffiths; Christopher J Larson; Dale E Mais; Keith Marschke; Jon Rosen; Eric Vajda; Lin Zhi; Andres Negro-Vilar
Journal: Proc Natl Acad Sci U S A Date: 2007-11-21 Impact factor: 11.205

4. Structure-activity relationships and X-ray structures describing the selectivity of aminopyrazole inhibitors for c-Jun N-terminal kinase 3 (JNK3) over p38.

Authors: Ted Kamenecka; Jeff Habel; Derek Duckett; Weimin Chen; Yuan Yuan Ling; Bozena Frackowiak; Rong Jiang; Youseung Shin; Xinyi Song; Philip LoGrasso
Journal: J Biol Chem Date: 2009-03-04 Impact factor: 5.157

Design of potent and selective 2-aminobenzimidazole-based p38alpha MAP kinase inhibitors with excellent in vivo efficacy.

1. p38 mitogen-activated protein kinase promotes cell survival in response to DNA damage but is not required for the G(2) DNA damage checkpoint in human cancer cells.

Review 2. Interleukins in glioblastoma pathophysiology: implications for therapy.

3. Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein-protein interaction profile.

4. Structure-activity relationships and X-ray structures describing the selectivity of aminopyrazole inhibitors for c-Jun N-terminal kinase 3 (JNK3) over p38.

5. Rapid and quantitative detection of p38 kinase pathway in mouse blood monocyte.

6. 1-Prop-2-ynyl-1H-benzimidazol-2-amine.

Review 7. The p38 mitogen-activated protein kinase signaling cascade in CD4 T cells.