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

• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm8005417

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.