Bioorg Med Chem Lett. 2010 Oct 1;20(19):5864-8. Epub 2010 Jul 30.

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

Lin S, Wrobleski ST, Hynes J Jr, Pitt S, Zhang R, Fan Y, Doweyko AM, Kish KF, Sack JS, Malley MF, Kiefer SE, Newitt JA, McKinnon M, Trzaskos J, Barrish JC, Dodd JH, Schieven GL, Leftheris K.

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Department of Immunology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.

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 p38 α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.

PMID:: 20732813; [PubMed - indexed for MEDLINE]

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Structures reported by this article

P38 Alpha Kinase Complexed With A 2-Aminothiazol-5-Yl-Pyrimidine Based Inhibitor

PDB: 3NWW

Source: Homo sapiens

Method: X-Ray Diffraction

Resolution: 2.09 Å

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

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