posted on 2023-11-21, 20:16authored byVadim Markovtsov, Matthew A. J. Duncton, Art Bagos, Sothy Yi, Sylvia Braselmann, Somasekhar Bhamidipati, Ihab S. Darwish, Jiaxin Yu, Alexander M. Owyang, Beth Fernandez, Bhushan Samant, Gary Park, Esteban S. Masuda, Simon J. Shaw
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.