- Design, synthesis, and biological testing of potential heme-coordinating nitric oxide synthase inhibitors
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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.,Martasek, Pavel,Roman, Linda J.,Silverman, Richard B.
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p. 3185 - 3198
(2007/10/03)
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- Non-peptide bombesin receptor antagonists
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The compounds of the instant invention are novel compounds of Formula I or a pharmaceutically acceptable salt thereof wherein Ar is phenyl or pyridyl unsubstituted or substituted. Ar1can be independently selected from Ar and can also include pyridyl-N-oxide, indolyl, imidazole, and pyridyl; R3can be independently selected from Ar or is hydrogen, hydroxy, NMe2, N-methyl-pyrrole, imidazole, tetrazole, thiazole (a), (b), (c), or (d), wherein Ar2is phenyl or pyridyl. The instant compounds antagonize the bombesin receptors in mammals and are therefore effective in treating and/or preventing depression, psychoses, seasonal affective disorders, cancer, feeding disorders, gastrointestinal disorders, inflammatory bowel disease, sleep disorders, and memory impairment.
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