title: N-Phenylbenzamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore.
abstract: Persistent opening of the mitochondrial permeability transition pore (PTP), an inner membrane channel, leads to mitochondrial dysfunction and renders the PTP a therapeutic target for a host of life-threatening diseases. Herein, we report our effort toward identifying small-molecule inhibitors of this target through structure-activity relationship optimization studies, which led to the identification of several potent analogues around the N-phenylbenzamide compound series identified by high-throughput screening. In particular, compound 4 (3-(benzyloxy)-5-chloro-N-(4-(piperidin-1-ylmethyl)phenyl)benzamide) displayed noteworthy inhibitory activity in the mitochondrial swelling assay (EC50 =280 nm), poor-to-very-good physicochemical as well as in vitro pharmacokinetic properties, and conferred very high calcium retention capacity to mitochondria. From the data, we believe compound 4 in this series represents a promising lead for the development of PTP inhibitors of pharmacological relevance.
authors.affiliation: University of Kansas Specialized Chemistry Center, 2034 Becker Drive, Lawrence, KS, 66049, USA. s.roy@unc.edu.|Division of Chemical Biology and Medicinal Chemistry and the Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA. s.roy@unc.edu.
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Roy
authors.affiliation: CNR Neuroscience Institute and Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, Padova, 35131, Italy.
authors.forename: Justina
authors.initials: J
authors.lastname: Šileikytė
authors.affiliation: University of Kansas Specialized Chemistry Center, 2034 Becker Drive, Lawrence, KS, 66049, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Neuenswander
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hedrick
authors.affiliation: Office of Translation to Practice, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Thomas D Y
authors.initials: TD
authors.lastname: Chung
authors.affiliation: University of Kansas Specialized Chemistry Center, 2034 Becker Drive, Lawrence, KS, 66049, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
authors.affiliation: University of Kansas Specialized Chemistry Center, 2034 Becker Drive, Lawrence, KS, 66049, USA. schoenen@ku.edu.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Schoenen
authors.affiliation: Vollum Institute, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. forte@ohsu.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Forte
authors.affiliation: CNR Neuroscience Institute and Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, Padova, 35131, Italy. bernardi@bio.unipd.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
mesh_terms: D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D000083162:Mitochondrial Permeability Transition Pore; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore
keywords: N-phenylbenzamides; calcium retention capacity; mitochondria; mitochondrial swelling; permeability transition