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

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Herberich B, Cao GQ, Chakrabarti PP, Falsey JR, Pettus L, Rzasa RM, Reed AB, Reichelt A, Sham K, Thaman M, Wurz RP, Xu S, Zhang D, Hsieh F, Lee MR, Syed R, Li V, Grosfeld D, Plant MH, Henkle B, Sherman L, Middleton S, Wong LM, Tasker AS

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

J Med Chem. 2008 Oct 23;51(20):6271-9. doi: 10.1021/jm8005417. Epub 2008 Sep 26.

PubMed ID

18817365 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
N-cyclopropyl-4-methyl-3-[1-(2-methylphenyl)phthalazin-6-yl]benzamide	Mitogen-activated protein kinase 14	IC 50 (nM)	0.8	N/A	N/A	Details
N-cyclopropyl-4-methyl-3-{2-[(2-morpholin-4-ylethyl)amino]quinazolin-6-yl}benzamide	Mitogen-activated protein kinase 14	IC 50 (nM)	2.4	N/A	N/A	Details