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

2008; American Chemical Society; Volume: 51; Issue: 20 Linguagem: Inglês

10.1021/jm8005417

1520-4804

Brad Herberich, Guoqiang Cao, Partha Chakrabarti, James R. Falsey, Liping H. Pettus, Robert M. Rzasa, Anthony B. Reed, Andreas Reichelt, Kelvin Sham, Maya Thaman, Ryan P. Wurz, Shimin Xu, Dawei Zhang, Faye Hsieh, Matthew R. Lee, Rashid Syed, Vivian Li, David Grosfeld, Matthew Plant, Bradley Henkle, Lisa Sherman, Scot Middleton, Lu Min Wong, Andrew S. Tasker,

Synthesis and biological activity

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.