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

Walker D.P., Bi F.C., Kalgutkar A.S., Bauman J.N., Zhao S.X., Soglia J.R., Aspnes G.E., Kung D.W., Klug-McLeod J., Zawistoski M.P., McGlynn M.A., Oliver R., Dunn M., Li J.C., Richter D.T., Cooper B.A., Kath J.C., Hulford C.A., Autry C.L., Luzzio M.J., Ung E.J., Roberts W.G., Bonnette P.C., Buckbinder L., Mistry A., Griffor M.C., Han S., Guzman-Perez A.

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.

Bioorg. Med. Chem. Lett. 18:6071-6077(2008) [PubMed] [Europe PMC]

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