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.

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