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Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor.
Luckhurst, Christopher A; Aziz, Omar; Beaumont, Vahri; Bürli, Roland W; Breccia, Perla; Maillard, Michel C; Haughan, Alan F; Lamers, Marieke; Leonard, Phil; Matthews, Kim L; Raphy, Gilles; Stott, Andrew J; Munoz-Sanjuan, Ignacio; Thomas, Beth; Wall, Michael; Wishart, Grant; Yates, Dawn; Dominguez, Celia.
Afiliación
  • Luckhurst CA; Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • Aziz O; Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • Beaumont V; CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 700, Los Angeles, CA 90045, United States.
  • Bürli RW; Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • Breccia P; Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • Maillard MC; CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 700, Los Angeles, CA 90045, United States. Electronic address: Michel.Maillard@chdifoundation.org.
  • Haughan AF; Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • Lamers M; Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • Leonard P; Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • Matthews KL; Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • Raphy G; Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • Stott AJ; Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • Munoz-Sanjuan I; CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 700, Los Angeles, CA 90045, United States.
  • Thomas B; Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • Wall M; Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • Wishart G; Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • Yates D; Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • Dominguez C; CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 700, Los Angeles, CA 90045, United States.
Bioorg Med Chem Lett ; 29(1): 83-88, 2019 01 01.
Article en En | MEDLINE | ID: mdl-30463802
We have identified a potent, cell permeable and CNS penetrant class IIa histone deacetylase (HDAC) inhibitor 22, with >500-fold selectivity over class I HDACs (1,2,3) and ∼150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. Dose escalation pharmacokinetic analysis demonstrated that upon oral administration, compound 22 can reach exposure levels in mouse plasma, muscle and brain in excess of cellular class IIa HDAC IC50 levels for ∼8 h. Given the interest in aberrant class IIa HDAC function for a number of neurodegenerative, neuromuscular, cardiac and oncology indications, compound 22 (also known as CHDI-390576) provides a selective and potent compound to query the role of class IIa HDAC biology, and the impact of class IIa catalytic site occupancy in vitro and in vivo.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Histona Desacetilasas / Histona Desacetilasas / Ácidos Hidroxámicos Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Histona Desacetilasas / Histona Desacetilasas / Ácidos Hidroxámicos Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Reino Unido