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

AI Article Synopsis

  • - The Rho kinase (ROCK) pathway is linked to various neurological diseases, particularly Huntington's disease (HD), where it contributes to mutant huntingtin protein aggregation and neurotoxicity.
  • - Researchers aimed to develop a potent and selective ROCK inhibitor that can effectively penetrate the central nervous system and can be taken orally while avoiding interference with other kinases like protein kinase G (PKG).
  • - The study details the optimization of existing compounds, leading to the discovery of a new series of ROCK inhibitors based on a piperazine structure, which showed strong effectiveness in inhibiting a ROCK target after oral administration.

Article Abstract

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.

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Source
http://dx.doi.org/10.1021/acs.jmedchem.2c00474DOI Listing

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