Hydroxyethylene isosteres of selective neuronal nitric oxide synthase inhibitors.
Nitric oxide (NO) is an important second messenger molecule for blood pressure homeostasis, as a neurotransmitter, and in the immune defense system. Excessive NO can lead to neurodegeneration and connective tissue damage. Three different isozymes of the enzyme nitric oxide synthase regulate NO production in endothelial (eNOS), neuronal (nNOS), and macrophage (iNOS) cells. Whereas creating a lower level of NO in some cells could be beneficial, it also could be detrimental to the protective effects that NO has on other cells. Therefore, it is essential that therapeutic NOS inhibitors be made that are subtype selective. Previously, we reported a series of nitroarginine-containing dipeptide amides as potent and selective nNOS inhibitors. Here we synthesize peptidomimetic hydroxyethylene isosteres of these dipeptide amides for potential increased bioavailability. None of the compounds is as potent or selective as the dipeptide amides, but they exhibit good inhibition and selectivity. When the terminal amino group was converted to a hydroxyl group, potency and selectivity greatly diminished, supporting the importance of the terminal amino group for binding.
Erdal
Erik P
EP
Department of Chemistry, Department of Biochemistry, Molecular Biology, and Cell Biology, and 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
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005030:Ethylenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D018716:Molecular Mimicry; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D004151:Dipeptides; D004791:Enzyme Inhibitors; D005030:Ethylenes; D009569:Nitric Oxide; C067254:hydroxyethylene; D052248:Nitric Oxide Synthase Type I