N-Phenylbenzamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore

Sudeshna Roy, Justina Šileikyte, Benjamin Neuenswander, Michael P. Hedrick, Thomas D.Y. Chung, Jeffrey Aubé, Frank J. Schoenen, Michael A. Forte, Paolo Bernardi

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)283-288
Number of pages6
JournalChemMedChem
Volume11
Issue number3
DOIs
StatePublished - Feb 4 2016

Keywords

  • N-phenylbenzamides
  • calcium retention capacity
  • mitochondria
  • mitochondrial swelling
  • permeability transition

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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  • Cite this

    Roy, S., Šileikyte, J., Neuenswander, B., Hedrick, M. P., Chung, T. D. Y., Aubé, J., Schoenen, F. J., Forte, M. A., & Bernardi, P. (2016). N-Phenylbenzamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore. ChemMedChem, 11(3), 283-288. https://doi.org/10.1002/cmdc.201500545