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Tuning the Reactivity of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators for Optimal in Vivo Efficacy.
Markovtsov, Vadim; Duncton, Matthew A J; Bagos, Art; Yi, Sothy; Braselmann, Sylvia; Bhamidipati, Somasekhar; Darwish, Ihab S; Yu, Jiaxin; Owyang, Alexander M; Fernandez, Beth; Samant, Bhushan; Park, Gary; Masuda, Esteban S; Shaw, Simon J.
Afiliação
  • Markovtsov V; Rigel Pharmaceuticals, Inc., 611 Gateway Boulevard, Suite 900, South San Francisco, California 94080, United States.
  • Duncton MAJ; Rigel Pharmaceuticals, Inc., 611 Gateway Boulevard, Suite 900, South San Francisco, California 94080, United States.
  • Bagos A; Rigel Pharmaceuticals, Inc., 611 Gateway Boulevard, Suite 900, South San Francisco, California 94080, United States.
  • Yi S; Rigel Pharmaceuticals, Inc., 611 Gateway Boulevard, Suite 900, South San Francisco, California 94080, United States.
  • Braselmann S; Rigel Pharmaceuticals, Inc., 611 Gateway Boulevard, Suite 900, South San Francisco, California 94080, United States.
  • Bhamidipati S; Rigel Pharmaceuticals, Inc., 611 Gateway Boulevard, Suite 900, South San Francisco, California 94080, United States.
  • Darwish IS; Rigel Pharmaceuticals, Inc., 611 Gateway Boulevard, Suite 900, South San Francisco, California 94080, United States.
  • Yu J; Rigel Pharmaceuticals, Inc., 611 Gateway Boulevard, Suite 900, South San Francisco, California 94080, United States.
  • Owyang AM; Rigel Pharmaceuticals, Inc., 611 Gateway Boulevard, Suite 900, South San Francisco, California 94080, United States.
  • Fernandez B; Rigel Pharmaceuticals, Inc., 611 Gateway Boulevard, Suite 900, South San Francisco, California 94080, United States.
  • Samant B; Rigel Pharmaceuticals, Inc., 611 Gateway Boulevard, Suite 900, South San Francisco, California 94080, United States.
  • Park G; Rigel Pharmaceuticals, Inc., 611 Gateway Boulevard, Suite 900, South San Francisco, California 94080, United States.
  • Masuda ES; Rigel Pharmaceuticals, Inc., 611 Gateway Boulevard, Suite 900, South San Francisco, California 94080, United States.
  • Shaw SJ; Rigel Pharmaceuticals, Inc., 611 Gateway Boulevard, Suite 900, South San Francisco, California 94080, United States.
ACS Med Chem Lett ; 14(12): 1700-1706, 2023 Dec 14.
Article em En | MEDLINE | ID: mdl-38116420
ABSTRACT
Dimethyl fumarate 1 is approved for the treatment of multiple sclerosis but is also associated with off-target activation of the niacin receptor. By using a tetrazolone or triazolone bioisostere approach to the fumarate and vinyl sulfone series of Nrf2 activators, we have optimized the electrophilicity of the double bond to tune the on-target Nrf2 activation with PK properties to achieve efficacy in animal models of multiple sclerosis. The study linked highly potent, highly electrophilic molecules to low plasma stability and, subsequently, limited efficacy. By contrast, a sulfonylvinyltriazolone 17 retains on-target potency but shows much weaker electrophilic potential. As a consequence, in vivo high exposures of 17 are obtained, resulting in efficacy in the EAE model similar to that observed for DMF. 17 (R079) is Ames negative, is not cytotoxic to cells, and shows little inhibition of either the niacin receptor or a panel of off-target receptors.

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: ACS Med Chem Lett Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: ACS Med Chem Lett Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos