Open AccessDiscovery of 6-Phenylhexanamide Derivatives as Potent Stereoselective Mitofusin Activators for the Treatment of Mitochondrial Diseases
Author(s) -
Xiawei Dang,
Lihong Zhang,
Antonietta Franco,
Jiajia Li,
Agostinho G. Rocha,
Sriram Devanathan,
Roland E. Dolle,
Peter R Bernstein,
Gerald W. Dorn
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c00366
Subject(s) - chemistry , adme , pharmacokinetics , mfn2 , pharmacology , bioavailability , mitochondrial fusion , in vivo , potency , fusion protein , computational biology , biochemistry , in vitro , gene , biology , genetics , mitochondrial dna , recombinant dna
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.