2. Academic Validation
  3. Identification of a Potent, Selective, and Brain-Penetrant Rho Kinase Inhibitor and its Activity in a Mouse Model of Huntington's Disease

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

  • J Med Chem. 2022 Jul 28;65(14):9819-9845. doi: 10.1021/acs.jmedchem.2c00474.
Tammy Ladduwahetty 1,  Matthew R Lee 2,  Michel C Maillard 2,  Roger Cachope 2,  Daniel Todd 1,  Michael Barnes 1,  Vahri Beaumont 2,  Alka Chauhan 1,  Caroline Gallati 1,  Alan F Haughan 1,  Georg Kempf 3,  Christopher A Luckhurst 1,  Kim Matthews 1,  George McAllister 1,  Philip Mitchell 1,  Hiral Patel 1,  Mark Rose 2,  Elizabeth Saville-Stones 1,  Stefan Steinbacher 3,  Andrew J Stott 1,  Emma Thatcher 1,  Jason Tierney 1,  Liudvikas Urbonas 1,  Ignacio Munoz-Sanjuan 2,  Celia Dominguez 2
Affiliations

Affiliations

  • 1 Discovery from Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K.
  • 2 CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 90045, United States.
  • 3 Proteros Biostructures GmbH, Bunsenstr. 7a, D-82152 Planegg-Martinsried, Germany.
PMID: 35816678 DOI: 10.1021/acs.jmedchem.2c00474
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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