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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.
Bioorg Med Chem Lett ; 18(23): 6071-7, 2008 Dec 01.
Article in En | MEDLINE | ID: mdl-18951788
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 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.
Subject(s)

Full text: 1 Database: MEDLINE Main subject: Pyrimidines / Focal Adhesion Kinase 2 Limits: Animals / Humans Language: En Year: 2008 Type: Article

Full text: 1 Database: MEDLINE Main subject: Pyrimidines / Focal Adhesion Kinase 2 Limits: Animals / Humans Language: En Year: 2008 Type: Article