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, <b>13</b>, with the potency, selectivity, and oral bioavailability of a preclinical candidate. Studies of <b>13</b> <i>cis</i>- and <i>trans</i>-4-hydroxycyclohexyl isostereomers unexpectedly revealed functionality and protein engagement exclusively for the trans form, <b>13B</b>. Preclinical absorption, distribution, metabolism, and excretion (ADME) and <i>in vivo</i> target engagement studies of <b>13B</b> support further development of 6-phenylhexanamide derivatives as therapeutic agents for human CMT2A.