Tammy Ladduwahetty, Matthew R Lee, Michel C Maillard, Roger Cachope, Daniel Todd, Michael Barnes, Vahri Beaumont, Alka Chauhan, Caroline Gallati, Alan F Haughan, Georg Kempf, Christopher A Luckhurst, Kim Matthews, George McAllister, Philip Mitchell, Hiral Patel, Mark Rose, Elizabeth Saville-Stones, Stefan Steinbacher, Andrew J Stott, Emma Thatcher, Jason Tierney, Liudvikas Urbonas, Ignacio Munoz-Sanjuan, Celia Dominguez
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...
July 11, 2022: Journal of Medicinal Chemistry