Identification of a Potent, Selective, and Brain-Penetrant Rho Kinase Inhibitor and its Activity in a Mouse Model of Huntington’s Disease

The Rho kinase (ROCK) pathway is implicated in the pathogenesis
of several conditions, including neurological diseases. In Huntington’s
disease (HD), ROCK is implicated in mutant huntingtin (HTT) aggregation
and neurotoxicity, and members of the ROCK pathway are increased in
HD mouse models and patients. To validate this mode of action as a
potential treatment for HD, we sought a potent, selective, central
nervous system (CNS)-penetrant ROCK inhibitor. Identifying a compound
that could be dosed orally in mice with selectivity against other
AGC kinases, including protein kinase G (PKG), whose inhibition could
potentially activate the ROCK pathway, was paramount for the program.
We describe the optimization of published ligands to identify a novel
series of ROCK inhibitors based on a piperazine core. Morphing of
the early series developed in-house by scaffold hopping enabled the
identification of a compound exhibiting high potency and desired selectivity
and demonstrating a robust pharmacodynamic (PD) effect by the inhibition
of ROCK-mediated substrate (MYPT1) phosphorylation after oral dosing.