Discovery of 6-Phenylhexanamide Derivatives as Potent Stereoselective Mitofusin Activators for the Treatment of Mitochondrial Diseases
- 8 June 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (13), 7033-7051
- https://doi.org/10.1021/acs.jmedchem.0c00366
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 13cis- 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.Keywords
Funding Information
- National Institute of Neurological Disorders and Stroke (R41NS113642, R41NS115184)
- China Scholarship Council
- National Institutes of Health (R35135736)
- Muscular Dystrophy Association (628906)
This publication has 30 references indexed in Scilit:
- MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2AScience, 2018
- Correcting mitochondrial fusion by manipulating mitofusin conformationsNature, 2016
- Mitochondrial Fission and Fusion Factors Reciprocally Orchestrate Mitophagic Culling in Mouse Hearts and Cultured FibroblastsCell Metabolism, 2015
- Mitochondrial Fusion Directs Cardiomyocyte Differentiation via Calcineurin and Notch SignalingScience, 2013
- Design of a Highly Selective and Potent Class of Non-planar Estrogen Receptor β AgonistsChemMedChem, 2013
- Fusion and Fission: Interlinked Processes Critical for Mitochondrial HealthAnnual Review of Genetics, 2012
- Mitochondrial Fusion is Essential for Organelle Function and Cardiac HomeostasisCirculation Research, 2011
- Requirements for a lead compound to become a clinical candidateBMC Neuroscience, 2008
- Mitochondrial fragmentation in neurodegenerationNature Reviews Neuroscience, 2008
- Fast Calculation of Molecular Polar Surface Area as a Sum of Fragment-Based Contributions and Its Application to the Prediction of Drug Transport PropertiesJournal of Medicinal Chemistry, 2000