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

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...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 51; no. 20; pp. 6271 - 6279
Main Authors:	Herberich, Brad, Cao, Guo-Qiang, Chakrabarti, Partha P, Falsey, James R, Pettus, Liping, Rzasa, Robert M, Reed, Anthony B, Reichelt, Andreas, Sham, Kelvin, Thaman, Maya, Wurz, Ryan P, Xu, Shimin, Zhang, Dawei, Hsieh, Faye, Lee, Matthew R, Syed, Rashid, Li, Vivian, Grosfeld, David, Plant, Matthew H, Henkle, Bradley, Sherman, Lisa, Middleton, Scot, Wong, Lu Min, Tasker, Andrew S
Format:	Journal Article
Language:	English
Published:	Columbus, OH American Chemical Society 23-10-2008
Subjects:	Animals Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Cells, Cultured Crystallography, X-Ray Drug Evaluation, Preclinical Humans Medical sciences Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors Mitogen-Activated Protein Kinase 14 - chemistry Mitogen-Activated Protein Kinase 14 - metabolism Models, Molecular Molecular Structure Pharmacology. Drug treatments Phthalazines - chemical synthesis Phthalazines - chemistry Phthalazines - pharmacology Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Quinolines - chemical synthesis Quinolines - chemistry Quinolines - pharmacology Rats Sensitivity and Specificity Structure-Activity Relationship Intravenous administration Rat Nitrogen heterocycle Diseases of the osteoarticular system Arthritis Selectivity Structure activity relation Bicyclic compound Aromatic compound Antirheumatic agent Chemical synthesis Tumor necrosis factor α Enzyme Transferases Rodentia Antiinflammatory agent Cytokine Oral administration Enzyme inhibitor Mitogen-activated protein kinase In vitro Phthalazine derivatives In vivo Vertebrata Chemotherapy Experimental disease Mammalia Treatment Animal Carboxamide Pharmacokinetics
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Summary:	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.
Bibliography:	ark:/67375/TPS-JCR8C3W9-L istex:F134F04E81FFCD62DD8B1A41FB366E9146E7CEF7 Table of elemental analysis results of compounds 8 and 15−17, HPLC analyses of compounds 1, 7, 9, 10, and 18−20, SFC analysis of 16 and 17, and crystal X-ray structure data for 1 and 19. This material is available free of charge via the Internet at http://pubs.acs.org. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm8005417