N-methyl-d-aspartate receptor channel blockers and method for identifying such

• US 6,251,854 B1
• Filed: 12/06/1999
• Issued: 06/26/2001
• Est. Priority Date: 03/20/1997
• Status: Expired due to Fees

• Current Assignee: Antonio Ferrer-Montiel, Jaime Merino, Mauricio Montal, Richard Houghten, Sylvie Blondelle
• Original Assignee: Antonio Ferrer-Montiel, Jaime Merino, Mauricio Montal, Richard Houghten, Sylvie Blondelle
• Inventors: Merino, Jaime, Houghten, Richard, Montal, Mauricio, Blondelle, Sylvie, Ferrer-Montiel, Antonio
• Primary Examiner(s): DAVENPORT, AVIS MICHELLE
• Application Number:
  US09/381,434
• Time in Patent Office: 568 Days
• Field of Search: 514/2, 514/17, 514/18, 514/19, 514/212, 514/238, 514/634
• US Class Current: 514/17.3
• CPC Class Codes: A61K 31/4188 condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07K 5/06095 Arg-amino acid
• CPC Class Codes: C07K 5/0817 the first amino acid being Arg
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids

Abstract

Compounds that provide protection against excitotoxic neuronal damage are selected from the group consisting of Arg-rich oligopeptides and compounds of formula 1:

where R₁ is alkyl, alkenyl, or hydroxyalkyl, aminoalkyl, or alkoxy-alkyl; and R₂ and R₃ are each natural or artificial amino acid side chains.

Claims

1. An NMDA channel blocker, selected from the group consisting of

a oligopeptide of the formula:

2. The oligopeptide of claim 1, wherein Xa is acetyl.

3. The oligopeptide of claim 2, wherein said oligopeotide is selected from the group consisting of Ac-MCRRKR and Ac-LCRRKF.

4. The oligopeptide of claim 1, wherein Xa is H.

5. The oligopeptide of claim 4, wherein X₆ comprises an indole-containing amino acid.

6. The oligopeptide of claim 4, wherein X₆ comprises D-Trp or L-Trp.

7. The oligopeptide of claim 6, wherein at least one of said guanidinium-containing amino acids comprises D-Arg or L-Arg.

8. The oligopeptide of claim 7, wherein said oligopeptide is selected from the group consisting of;

RRRRW, RRRCRW, RRRRWW, RRRCWW, RRCRRW, RRCCRW, RCRRRW, RCRCRW, RCRRWW, RCRCWW, RCCRRW, and RCCCRW.

9. The oligopeptide of claim 1, wherein said oligopeptide is selected from the group consisting of RR, RW, RRR, RRW, RRRRRR, D-Arg-D-Arg-D-Arg-D-Trp-D-Arg-D-Phe, and D-Arg-D-Arg-D-Arg-D-Arg-D-Trp-D-Trp.

10. The compound of claim 1, wherein R₁ is —

(CH₂)_nCR_aR_bR_c, where n is an integer from 0 to about 8, and R_a, R_b, and R_c are each independently CH₃, CH₃CH₂, halo, or H.

11. The compound of claim 1, wherein R₂ and R₃ are each independently selected from the group consisting of 3-guanadinylpropyl, 4-guanadinylbutyl, 3-guanadinylbutyl, 2-guanadinylethyl, 1-methylpropyl, 2-methylpropyl, propyl,

where m is an integer from 0 to 3, R_d is a substituent selected from the group consisting of CH₃, CF₃, OH, NH₂, NO₂, SH, COOH, CONH₂, and halo.

12. The compound of claim 11, wherein R2 and R3 are each independently 3-guanadinylpropyl, 1-methylpropyl, or 4-fluorobenzyl.

13. The compound of claim 1, wherein said compound is selected from the group consisting of

2H-3- (4-fluorobenzyl) -7- (but-2-yl) -8- (3-methylbutyl)diazolidine[1,2-b]dihydroimidazole:

2H-3-(3-guanidinopropyl)-7-(3-guanidinopropyl)-8-(3-methylbutyl)diazolidine[1,2-b]dihydroimidazole;

2H-3-(3-guanidinopropyl)-7-(but-2-yl)-8-(3-methylbutyl)diazolidine[1,2-b]dihydroimidazole;

2H-3-(4-fluorobenzyl)-7-(3-guanidinopropyl)-8-(3-methylbutyl)diazolidine[1,2-b]dihydroimidazole; and

2H-3-(4-fluorobenzyl)-7-(t-butyl)-8-(3-methylbutyl) diazolidine[1,2-b]dihydroimidazole;

and a pharmaceutically acceptable salt thereof.

14. A method for treating exictotoxic neuronal death in a subject, comprising:

providing an NMDA channel blocker compound selected from the group consisting of

a oligopeptide of the formula;

15. The method of claim 14, wherein said NMDA channel blocker compound is selected from the group consisting of AC-MCRRKR, Ac-LCRRKF, RRRRW, RRRCRW, RRRRWW, RRRCWW, RRCRRW, RRCCRW, RCRRRW, RR, RW, RRR, RRW, RCRCRW, RCRRWW, RCRCWW, RCCRRW, RCCCRW, 2H-3- (4-fluorobenzyl)-7-(but-2-yl)-8- (3-methylbutyl)diazolidine[1,2-b]dihydroimidazole:

2H-3-(3-guanidinopropyl)-7-(3-guanidinopropyl)-8-(3-methylbutyl)diazolidine[1,2-b]dihydroimidazole;

2H-3-(3-guanidinopropyl)-7-(but-2-yl)-8-(3-methyl-butyl)diazolidine[1,2-b]dihydroimidazole;

2H-3-(4-fluorobenzyl)-7-(3-guanidinopropyl)-8-(3-methylbutyl)diazolidine[1,2-b]dihydroimidazole; and

2H-3-(4-fluorobenzyl)-7-(t-butyl)-8-(3-methylbutyl)diazolidine[1,2-b]dihydroimidazole; and

a pharmaceutically acceptable salt thereof.