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

Graphical Abstract

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.

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.