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

• Published in: ChemMedChem Vol. 11; no. 3; pp. 283 - 288
• Main Authors: Roy, Sudeshna, Šileikytė, Justina, Neuenswander, Benjamin, Hedrick, Michael P., Chung, Thomas D. Y., Aubé, Jeffrey, Schoenen, Frank J., Forte, Michael A., Bernardi, Paolo
• Format: Journal Article
• Language: English
• Published: Germany Blackwell Publishing Ltd 04-02-2016; Wiley Subscription Services, Inc
• Subjects: Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; calcium retention capacity; Dose-Response Relationship, Drug; Humans; mitochondria; Mitochondrial DNA; Mitochondrial Membrane Transport Proteins - antagonists & inhibitors; Mitochondrial Permeability Transition Pore; mitochondrial swelling; Molecular Structure; N-phenylbenzamides; Permeability; permeability transition; Rodents; Structure-Activity Relationship; mitochondrial swelling; permeability transition; calcium retention capacity; N-phenylbenzamides; mitochondria
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201500545

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.
Calcium deregulation adjourned: Persistent opening of the mitochondrial permeability transition pore (PTP), which is a Ca2+‐release mega channel, causes cell death. Here, we describe the discovery of potent N‐phenylbenzamide compounds as PTP inhibitors that confer very high calcium retention capacity to the mitochondria that also possess good‐to‐very‐good pharmacological profiles.