Potent and selective neuronal nitric oxide synthase inhibitors with improved cellular permeability.
Recently, a series of potent and selective neuronal nitric oxide synthase inhibitors containing two basic nitrogen atoms was reported (Ji, H.; Stanton, B. Z.; Igarashi, J.; Li, H.; Martásek, P.; Roman, L. J.; Poulos, T. L.; Silverman, R. B. J. Am. Chem. Soc. 2008, 130, 3900-3914). In an effort to improve their bioavailability, three compounds (2a-c) were designed with electron-withdrawing groups near one of the basic nitrogen atoms to lower its pK(a). Inhibition studies with these compounds showed that two of them not only retained most of the potency and selectivity of the best analogue of the earlier series, but also showed improved membrane permeability based on data from a cell-based assay.
Xue
Fengtian
F
Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
Fang
Jianguo
J
Lewis
William W
WW
Martásek
Pavel
P
Roman
Linda J
LJ
Silverman
Richard B
RB
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D052248:Nitric Oxide Synthase Type I