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 Forte, Paolo Bernardi

Research output: Contribution to journalArticle

20 Citations (Scopus)

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

Fingerprint

Mitochondria
Pharmacokinetics
Ion Channels
Swelling
Permeability
Assays
Screening
Throughput
Mitochondrial Swelling
Calcium
Molecules
Structure-Activity Relationship
Pharmacology
mitochondrial permeability transition pore
benzamide
Lead
Therapeutics
In Vitro Techniques

Keywords

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

ASJC Scopus subject areas

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

Cite this

Roy, S., Šileikyte, J., Neuenswander, B., Hedrick, M. P., Chung, T. D. Y., Aubé, J., ... 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

N-Phenylbenzamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore. / Roy, Sudeshna; Šileikyte, Justina; Neuenswander, Benjamin; Hedrick, Michael P.; Chung, Thomas D Y; Aubé, Jeffrey; Schoenen, Frank J.; Forte, Michael; Bernardi, Paolo.

In: ChemMedChem, Vol. 11, No. 3, 04.02.2016, p. 283-288.

Research output: Contribution to journalArticle

Roy, S, Šileikyte, J, Neuenswander, B, Hedrick, MP, Chung, TDY, Aubé, J, Schoenen, FJ, Forte, M & Bernardi, P 2016, 'N-Phenylbenzamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore', ChemMedChem, vol. 11, no. 3, pp. 283-288. https://doi.org/10.1002/cmdc.201500545
Roy S, Šileikyte J, Neuenswander B, Hedrick MP, Chung TDY, Aubé J et al. N-Phenylbenzamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore. ChemMedChem. 2016 Feb 4;11(3):283-288. https://doi.org/10.1002/cmdc.201500545
Roy, Sudeshna ; Šileikyte, Justina ; Neuenswander, Benjamin ; Hedrick, Michael P. ; Chung, Thomas D Y ; Aubé, Jeffrey ; Schoenen, Frank J. ; Forte, Michael ; Bernardi, Paolo. / N-Phenylbenzamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore. In: ChemMedChem. 2016 ; Vol. 11, No. 3. pp. 283-288.
@article{e41a94ca37b74b199968415c27185f06,
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.",
keywords = "calcium retention capacity, mitochondria, mitochondrial swelling, N-phenylbenzamides, permeability transition",
author = "Sudeshna Roy and Justina Šileikyte and Benjamin Neuenswander and Hedrick, {Michael P.} and Chung, {Thomas D Y} and Jeffrey Aub{\'e} and Schoenen, {Frank J.} and Michael Forte and Paolo Bernardi",
year = "2016",
month = "2",
day = "4",
doi = "10.1002/cmdc.201500545",
language = "English (US)",
volume = "11",
pages = "283--288",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

TY - JOUR

T1 - N-Phenylbenzamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore

AU - Roy, Sudeshna

AU - Šileikyte, Justina

AU - Neuenswander, Benjamin

AU - Hedrick, Michael P.

AU - Chung, Thomas D Y

AU - Aubé, Jeffrey

AU - Schoenen, Frank J.

AU - Forte, Michael

AU - Bernardi, Paolo

PY - 2016/2/4

Y1 - 2016/2/4

N2 - 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.

AB - 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.

KW - calcium retention capacity

KW - mitochondria

KW - mitochondrial swelling

KW - N-phenylbenzamides

KW - permeability transition

UR - http://www.scopus.com/inward/record.url?scp=84957428633&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84957428633&partnerID=8YFLogxK

U2 - 10.1002/cmdc.201500545

DO - 10.1002/cmdc.201500545

M3 - Article

C2 - 26693836

AN - SCOPUS:84957428633

VL - 11

SP - 283

EP - 288

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

IS - 3

ER -