Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): structure–activity relationships and strategies for the elimination of reactive …

…, J Klug-McLeod, MP Zawistoski, MA McGlynn…

Index: 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 Bioorganic and Medicinal Chemistry Letters, 2008 , vol. 18, # 23 p. 6071 - 6077

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Citation Number: 42

Abstract

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 ...