Development of amino-pyrimidine inhibitors of c-Jun N-terminal kinase (JNK): Kinase profiling guided optimization of a 1,2,3-benzotriazole lead

Structure and kinase profiling guided the optimization of a CDK2 1,2,3-benzotriazole hit to give a series of indoles that are selective and potent dual JNK1 and 2 inhibitors. An advanced compound, 24f (IC50 JNK1/2=16/66nM), was developed and suitable for in vivo pharmacological evaluation of JNK inhibition. A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC50=16 and 66nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.