Design, synthesis, and biological testing of potential heme-coordinating nitric oxide synthase inhibitors.
Based on computer modeling of the active site of nitric oxide synthases (NOS), a series of 10 amidine compounds (9-18) was designed including potential inhibitors that involve the coordination of side-chain functional groups with the iron of the heme cofactor. The most potent and selective compound was the methylthio amidine analogue 9, which was more potent than L-nitroarginine with 185-fold selectivity for inhibition of neuronal NOS over endothelial NOS. It also exhibited time-dependent inhibition, but did not involve the mechanism previously proposed for other amidine inhibitors of NOS. None of the compounds, however, exhibited heme-binding characteristics according to absorption spectroscopy.
Litzinger
Elizabeth A
EA
Department of Chemistry, The Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, IL 60208-3113, USA.
Martásek
Pavel
P
Roman
Linda J
LJ
Silverman
Richard B
RB
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006418:Heme / Q000737:chemistry* / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051381:Rats; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D006418:Heme; D001120:Arginine; D019001:Nitric Oxide Synthase