N-Phenylbenzamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore.
ChemMedChem
; 11(3): 283-8, 2016 Feb 04.
Article
em En
| MEDLINE
| ID: mdl-26693836
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 =280â
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 compoundâ
4 in this series represents a promising lead for the development of PTP inhibitors of pharmacological relevance.
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Base de dados:
MEDLINE
Assunto principal:
Benzamidas
/
Proteínas de Transporte da Membrana Mitocondrial
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article