Discovery of 6-Phenylhexanamide Derivatives as Potent Stereoselective Mitofusin Activators for the Treatment of Mitochondrial Diseases.

ABSTRACT: Mutations in the mitochondrial fusion protein mitofusin (MFN) 2 cause the chronic neurodegenerative condition Charcot-Marie-Tooth disease type 2A (CMT2A), for which there is currently no treatment. Small-molecule activators of MFN1 and MFN2 enhance mitochondrial fusion and offer promise as therapy for this condition, but prototype compounds have poor pharmacokinetic properties. Herein, we describe a rational design of a series of 6-phenylhexanamide derivatives whose pharmacokinetic optimization yielded a 4-hydroxycyclohexyl analogue, 13, with the potency, selectivity, and oral bioavailability of a preclinical candidate. Studies of 13 cis- and trans-4-hydroxycyclohexyl isostereomers unexpectedly revealed functionality and protein engagement exclusively for the tr

SUBMITTER: Dang X 

PROVIDER: S-EPMC7731667 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature