1095648-01-3Relevant academic research and scientific papers
Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): Structure-activity relationships and strategies for the elimination of reactive metabolite formation
Walker, Daniel P.,Christopher Bi,Kalgutkar, Amit S.,Bauman, Jonathan N.,Zhao, Sabrina X.,Soglia, John R.,Aspnes, Gary E.,Kung, Daniel W.,Klug-McLeod, Jacquelyn,Zawistoski, Michael P.,McGlynn, Molly A.,Oliver, Robert,Dunn, Matthew,Li, Jian-Cheng,Richter, Daniel T.,Cooper, Beth A.,Kath, John C.,Hulford, Catherine A.,Autry, Christopher L.,Luzzio, Michael J.,Ung, Ethan J.,Roberts, W. Gregory,Bonnette, Peter C.,Buckbinder, Leonard,Mistry, Anil,Griffor, Matthew C.,Han, Seungil,Guzman-Perez, Angel
scheme or table, p. 6071 - 6077 (2009/08/07)
The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.
