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 trans form, 13B. Preclinical absorption, distribution, metabolism, and
excretion (ADME) and in vivo target engagement studies
of 13B support further development of 6-phenylhexanamide
derivatives as therapeutic agents for human CMT2A.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.