Selective neuronal nitric oxide synthase inhibitors
AssigneeNorthwestern University
InventorsRichard B. Silverman, Jung-Mi Hah, Jose Antonio Gomez Vidal
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Abstract
Peptidomimetic compositions for selective inhibition of neuronal nitric oxide synthase.
Claims23
An N-nitroarginine-containing dipeptide composition having the structural formula
- 12
- wherein R1 is selected from the group consisting of hydrogen, alkyl, and a prolinyl moiety;
- and R2 is selected from the group consisting of amino, alkyl, aminoalkyl, an aminoprolinamide moiety, and a diaminocyclopentanecarboxamide moiety.
A dipeptide composition comprising an N-nitroarginine (ArgNO2) residue coupled with an amide bond at a terminus of said nitroarginine residue to an amino-substituted proline (ProNH2) residue, said composition having a formula selected from the group consisting of:
- ArgNO2-ProNH2, wherein said substituted proline residue is coupled to the N-terminus of said nitroarginine residue;
- and
- ProNH2-ArgNO2-NH2, wherein said substituted proline residue is coupled to the C-terminus of said nitroarginine residue.
A method of using a proline residue to affect nitric oxide synthase inhibition, said method comprising:
- providing a dipeptide composition having an N-nitroarginine residue coupled with an amide bond at a terminus of said nitroarginine residue to an amino-substituted proline residue;
- and
- interacting said dipeptide composition with an isoform of nitric oxide synthase, said composition in an amount sufficient to inhibit nitric oxide synthase activity on an available arginine substrate.
A peptidomimetic N-nitroguanidinyl composition having the structural formula
- 13
- wherein R1 is XNHR2, and X is a moiety selected from the group consisting of CH2 and C(O);
- and R2 is selected from the group consisting of CH2(CH2)nNH2, where n=1-3;
- 14
- , where n=0-2;
- and
- 15
- , where m=0-2 and n=0-2.
A method of using amide bond reduction to affect nitric oxide synthase inhibition, said method comprising:
- providing an N-nitroarginine analog composition with a reduced amide bond, said composition having the structural formula
- 18
- wherein R1 is XNHR2, and X is a moiety selected from the group consisting of CH2 and C(O);
- and R2 is selected from the group consisting of CH2(CH2)nNH2, where n=1-3;
- 19
- , where n=0-2;
- and
- 20
- , where m=0-2 and n=0-2;
- and
- interacting said reduced amide analog composition with an isoform of nitric acid synthase, said composition in an amount sufficient to inhibit nitric oxide formation.
Dependencies are inferred from the claim text.