1. Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases
- Author
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Dana Gitnick, Gang Liu, Julia M. Ford Pulido, Mike A. Breider, Daniel K. Treiber, Joyce K. James, Robert C. Armstrong, Michael F. Gardner, Brian T. Campbell, Barbara A. Belli, Daniel Brigham, Mark W. Holladay, and Helen Hua
- Subjects
biology ,Kinase ,business.industry ,Growth factor ,medicine.medical_treatment ,Inflammatory arthritis ,Organic Chemistry ,Arthritis ,Pharmacology ,medicine.disease ,Biochemistry ,Pharmacokinetics ,In vivo ,Tolerability Study ,Drug Discovery ,biology.protein ,medicine ,business ,Platelet-derived growth factor receptor - Abstract
A series of potent, selective platelet-derived growth factor receptor-family kinase inhibitors was optimized starting from a globally selective lead molecule 4 through structural modifications aimed at improving the physiochemical and pharmacokinetic properties, as exemplified by 18b. Further clearance reduction via per-methylation of the α-carbons of a solubilizing piperidine nitrogen resulted in advanced leads 22a and 22b. Results from a mouse tumor xenograft, a collagen-induced arthritis model, and a 7 day rat in vivo tolerability study culminated in the selection of compound 22b (AC710) as a preclinical development candidate.
- Published
- 2012