期刊
CHEMMEDCHEM
卷 11, 期 3, 页码 283-288出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201500545
关键词
calcium retention capacity; mitochondria; mitochondrial swelling; N-phenylbenzamides; permeability transition
资金
- US National Institutes of Health (NIH)
- Telethon-Italy [GGP14037]
- NIH [U54HG005031, U54HG005033, R03A033978, U54HG005031-05S1]
- NIH Shared Instrumentation Grant [S10RR024664]
- US National Science Foundation (NSF) [0320648]
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=280nm), 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 compound4 in this series represents a promising lead for the development of PTP inhibitors of pharmacological relevance.
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