https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00366
https://www.ncbi.nlm.nih.gov/pubmed/32506913?dopt=Abstract
Discovery of 6-Phenylhexanamide Derivatives as Potent Stereoselective Mitofusin Activators for the Treatment of Mitochondrial Diseases.
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Discovery of 6-Phenylhexanamide Derivatives as Potent Stereoselective Mitofusin Activators for the Treatment of Mitochondrial Diseases.
J Med Chem. 2020 Jun 08;:
Authors: Dang X, Zhang L, Franco A, Li J, Rocha AG, Devanathan S, Dolle RE, Bernstein PR, Dorn Ii GW
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 rational design of a series of 6-phenylhexanamide derivatives whose pharma-cokinetic optimization yielded a 4-hydroxy cyclohexyl analog, 13, with the potency, selectivity, and oral bioavailability of a preclinical candidate. Studies of 13 cis- and trans- 4-hydroxy cyclohexyl isostereomers unexpectedly revealed functionality and protein engagement exclusively for the trans- form, 13B. Preclinical ADME and in vivo target engagement studies of 13B support further development of 6-phenylhexanamide derivatives as therapeutic agents for human CMT2A.
PMID: 32506913 [PubMed – as supplied by publisher]
PubMed:32506913
Dang X, Zhang L, Franco A, Li J, Rocha AG, Devanathan S, Dolle RE, Bernstein PR, Dorn Ii GW
