J Med Chem. 2008 Oct 23;51(20):6271-9. Epub 2008 Sep 26.

Discovery of highly selective and potent p38 inhibitors based on a phthalazine scaffold.

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Department of Medicinal Chemistry, Amgen, Inc., Thousand Oaks, California 91320-1799, USA. brad.herberich@amgen.com

Abstract

Investigations into the structure-activity relationships (SAR) of a series of phthalazine-based inhibitors of p38 are described. These efforts originated from quinazoline 1 and through rational design led to the development of a series of orally bioavailable, potent, and selective inhibitors. Kinase selectivity was achieved by exploiting a collection of interactions with p38alpha including close contact to Ala157, occupation of the hydrophobic gatekeeper pocket, and a residue flip with Gly110. Substitutions on the phthalazine influenced the pharmacokinetic properties, of which compound 16 displayed the most desirable profile. Oral dosing (0.03 mg/kg) of 16 in rats 1 h prior to LPS challenge gave a >50% decrease in TNFalpha production.

PMID:: 18817365; [PubMed - indexed for MEDLINE]

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Structures reported by this article

P38 Complexed With A Quinazoline Inhibitor

PDB: 3DT1

Source: Homo sapiens

Method: X-Ray Diffraction

Resolution: 2.8 Å

See all 2 structures...

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