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

被引：59

作者：

Herberich, Brad ^{[1
]}

Cao, Guo-Qiang ^{[1
]}

Chakrabarti, Partha P. ^{[1
]}

Falsey, James R. ^{[1
]}

Pettus, Liping ^{[1
]}

Rzasa, Robert M. ^{[1
]}

Reed, Anthony B. ^{[1
]}

Reichelt, Andreas ^{[1
]}

Sham, Kelvin ^{[1
]}

Thaman, Maya ^{[1
]}

Wurz, Ryan P. ^{[1
]}

Xu, Shimin ^{[1
]}

Zhang, Dawei ^{[1
]}

Hsieh, Faye ^{[2
]}

Lee, Matthew R. ^{[3
]}

Syed, Rashid ^{[3
]}

Li, Vivian ^{[3
]}

Grosfeld, David ^{[3
]}

Plant, Matthew H. ^{[4
]}

Henkle, Bradley ^{[4
]}

Sherman, Lisa ^{[4
]}

Middleton, Scot ^{[4
]}

Wong, Lu Min ^{[4
]}

Tasker, Andrew S. ^{[1
]}

机构：

[1] Amgen Inc, Dept Med Chem, Thousand Oaks, CA 91320 USA

[2] Amgen Inc, Dept Pharmacokinet & Drug Metab, Thousand Oaks, CA 91320 USA

[3] Amgen Inc, Dept Mol Struct, Thousand Oaks, CA 91320 USA

[4] Amgen Inc, Dept Inflammat, Thousand Oaks, CA 91320 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 20期

关键词：

D O I：

10.1021/jm8005417

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：6271 / 6279

页数：9

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