Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 51, Issue 20, Pages 6271-6279Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm8005417
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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 p38 alpha including close contact to Ala157, occupation of the hydrophobic gatekeeper pocket, and a residue flip with Gly 110. 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 TNF alpha production.
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