Discovery of Highly Selective and Potent p38 Inhibitors Based on a Phthalazine Scaffold

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• 作者：Brad Herberich ; Guo-Qiang Cao ; Partha P. Chakrabarti ; James R. Falsey ; Liping Pettus ; Robert M. Rzasa ; Anthony B. Reed ; Andreas Reichelt ; Kelvin Sham ; Maya Thaman ; Ryan P. Wurz ; Shimin Xu ; Dawei Zhang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：October 23, 2008
• 年：2008
• 卷：51
• 期：20
• 页码：6271-6279
• 全文大小：239K
• 年卷期：v.51,no.20(October 23, 2008)
• ISSN：1520-4804

文摘

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 p38α 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 TNFα production.