Inhibition of nitric oxide synthase by amino acids and dipeptides
AssigneeNorthwestern University
InventorsRichard B. Silverman, Hui Huang, Henry Q. Zhang
Life of this patent
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Abstract
Methods and compositions for inhibiting at least one isoform of nitric oxide synthase are provided. Pharmaceutical compositions include derivatives of arginine as well as dipeptides and dipeptide analogs that contain nitroarginine or another unnatural amino acid. Compositions can be used to selectively inhibit particular isoforms of nitric oxide synthase.
Claims7
A method of inhibiting the activity of neuronal nitric oxide synthase comprising contacting neuronal nitric oxide synthase with a dipeptide for a time and under conditions effective to inhibit the activity of neuronal nitric oxide synthase, wherein at least one of the two amino acids in the dipeptide is D- or L-Nitroarginine or an ester or amide derivative thereof.
A process for selectively inhibiting the activity of endothelial nitric oxide synthase and neuronal nitric oxide synthase relative to inducible nitric oxide synthase comprising exposing endothelial nitric oxide synthase, neuronal nitric oxide synthase and inducible nitric oxide synthase to an amino acid derivative of the formula Nω-R-L-Arginine, where R is a C2-C6 alkane or alkene for a time and under conditions effective to selectively inhibit the activity of endothelial nitric oxide synthase and neuronal nitric oxide synthase relative to inducible nitric oxide synthase.
A composition comprising a suitable diluent and a dipeptide, wherein the dipeptide is present in an amount effective to inhibit nitric oxide synthase, and wherein the dipeptide is selected from the group consisting of L-Nitroarginine-L-Phe-OMe, L-Nitroarginine-D-Phe-OMe, D-Nitroarginine-L-Phe-OMe, D-Nitroarginine-D-Phe-OMe, D-Phe-L-Nitroarginine-OMe, L-Phe-D-Nitroarginine-OMe, D-Phe-D-Nitroarginine-OMe, L-Phe-L-Nitroarginine-OMe, L-Nitroarginine-L-Phe-OBn, L-Phe-L-Nitroarginine-OBn, D-Phe-L-Nitroarginine, L-Nitroarginine-L-Phe, L-Phe-L-Nitroarginine, L-Nω-nitroarginine-L-lysine, L-Nω-nitroarginine-L-Nω-nitroarginine, L-lysine-D-Nω-nitroarginine, D-lysine-D-Nω-nitroarginine, L-histidine-D-Nω-nitroarginine, L-Nω-nitroarginine-D-glutamine, D-Nω-nitroarginine-L-serine, L-Nω-nitroarginine-D-asparagine, L-nitroArg-L-2,4-diaminobutanoic acid, L-nitroArg-L-Orn, L-nitroArg-L-2,3-diaminopropanoic acid, and D-Orn-D-nitroArg.
A composition comprising a suitable diluent and an amino acid derivative of the formula Nω-propyl-L-Arginine, wherein the amino acid derivative is present in an amount effective to inhibit nitric oxide synthase.
A process for selectively inhibiting the activity of neuronal nitric oxide synthase relative to endothelial nitric oxide synthase and inducible nitric oxide synthase comprising exposing endothelial nitric oxide synthase, neuronal nitric oxide synthase and inducible nitric oxide synthase to an amino acid derivative of the formula Nω-R-L-Arginine, where R is a C2-C6 alkane or alken for a time and under conditions effective to selectively inhibit the activity of neuronal nitric oxide synthase relative to endothelial nitric oxide synthase and inducible nitric oxide synthase.
Dependencies are inferred from the claim text.