Lead Optimization toward Proof-of-Concept Tools for Huntington’s Disease within a 4-(1H-Pyrazol-4-yl)pyrimidine Class of Pan-JNK Inhibitors
John Wityak, Kevin F. McGee, Michael P. Conlon, Renhua Song, Bryan C. Duffy, Brent Clayton, Michael A. Lynch, Gwen Wang, Emily Elsa Freeman, James C. Haber, Douglas B. Kitchen, David D. Manning, Jiffry Ismail, Yuri L. Khmelnitsky, Peter C. Michels, Jeff Webster, Macarena Irigoyen, Michele Luche, Monica Hultman, Mei Bai · Journal of Medicinal Chemistry · 2015
Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.