Ladduwahetty, Tammy; Lee, Matthew R.; Maillard, Michel C.; Cachope, Roger; Todd, Daniel; Barnes, Michael; Beaumont, Vahri; Chauhan, Alka; Gallati, Caroline; Haughan, Alan F.; Kempf, Georg; Luckhurst, Christopher A.; Matthews, Kim; McAllister, George; Mitchell, Philip; Patel, Hiral; Rose, Mark; Saville-Stones, Elizabeth; Steinbacher, Stefan; Stott, Andrew J.; Thatcher, Emma; Tierney, Jason; Urbonas, Liudvikas; Munoz-Sanjuan, Ignacio; Dominguez, Celia published the artcile< Identification of a Potent, Selective, and Brain-Penetrant Rho Kinase Inhibitor and its Activity in a Mouse Model of Huntington's Disease>, Quality Control of 870997-85-6, the main research area is piperazine analog preparation Rho kinase inhibitor SAR docking pharmacokinetics.
The Rho kinase (ROCK) pathway is implicated in the pathogenesis of several conditions, including neurol. 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, a potent, selective, central nervous system (CNS)-penetrant ROCK inhibitor was sought. 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. The optimization of published ligands to identify a novel series of ROCK inhibitors based on a piperazine core was demonstrated. Morphing of the early series developed inhouse 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.
Journal of Medicinal Chemistry published new progress about Molecular docking. 870997-85-6 belongs to class pyridine-derivatives, and the molecular formula is C6H5BrN2O2, Quality Control of 870997-85-6.