NPY peptide analogs

التفاصيل البيبلوغرافية
العنوان: NPY peptide analogs
Patent Number: 5,328,899
تاريخ النشر: July 12, 1994
Appl. No: 07/882,923
Application Filed: May 12, 1992
مستخلص: Human Neuropeptide Y (NPY) has the formula: H-Tyr-Pro-Ser-Lys-Pro-Asp-Asn-Pro-Gly-Glu-Asp-Ala-Pro- Ala-Glu-Asp-Met-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile- Thr-Arg-Gln-Arg -Tyr-NH.sub.2. Porcine and rat NPY have the same sequence except for Leu instead of Met in the 17-position. Porcine PYY is homologous having 11 different residues. NPY analogs and N-terminally-shortened fragments, e.g. NPY(18-36), which contain one or more specific D-isomer substitutions for the naturally occurring residues (as well as pharmaceutically acceptable salts thereof), dispersed in a pharmaceutically acceptable liquid or solid carrier, can be administered to mammals, including humans, to substantially lower blood pressure over an extended period of time or to counteract hypertension.
Inventors: Boublik, Jaroslav H. (Elwood, AUX); Rivier, Jean E. F. (La Jolla, CA); Brown, Marvin R. (Del Mar, CA); Scott, Neal A. (Atlanta, GA)
Assignees: The Salk Institute for Biological Studies (San Diego, CA), The Regents of the University of California (Oakland, CA)
Claim: What is claimed is
Claim: 1. A method for lowering the blood pressure of a mammal, which method comprises administering to said mammal an effective amount of a peptide or a nontoxic salt thereof, having one of the following formulae
Claim: (a) H-Ala-Arg-Tyr-Xaa.sub.21 -Xaa.sub.22 -Ala-Leu-Arg-His-Xaa.sub.27 -Ile-Xaa.sub.29 -Xaa.sub.30 -Xaa.sub.31 -Xaa.sub.32 -Arg-Xaa.sub.34 -Xaa.sub.35 -Xaa.sub.36 -NH.sub.2 wherein Xaa.sub.21 is Tyr or D-Tyr; Xaa.sub.22 is Ser or D-Ser; Xaa.sub.27 is Tyr or D-Tyr; Xaa.sub.29 is Asn or D-Asn; Xaa.sub.30 is Leu or D-Leu; Xaa.sub.31 is Ile or D-Ile; Xaa.sub.32 is Thr or D-Thr; Xaa.sub.34 is Gln or D-Gln; Xaa.sub.35 is Arg or D-Arg; and Xaa.sub.36 is Tyr or D-Tyr; and wherein one D-isomer is present from among Xaa.sub.21, Xaa.sub.22, Xaa.sub.27, Xaa.sub.29, Xaa.sub.30, Xaa.sub.31, Xaa.sub.32, Xaa.sub.34, Xaa.sub.35 and Xaa.sub.36 ; or
Claim: (b) H-Ser-Arg-Tyr-Xaa.sub.21 -Xaa.sub.22 -Ser-Leu-Arg-His-Xaa.sub.27 -Leu-Xaa.sub.29 -Xaa.sub.30 -Xaa.sub.31 -Xaa.sub.32 -Arg-Xaa.sub.34 -Xaa.sub.35 -Xaa.sub.36 -NH.sub.2, wherein Xaa.sub.21 is Tyr or D-Tyr; Xaa.sub.22 is Ala or D-Ala; Xaa.sub.27 is Tyr or D-Tyr; Xaa.sub.29 is Asn or D-Asn; Xaa.sub.30 is Leu or D-Leu; Xaa.sub.31 is Val or D-Val; Xaa.sub.32 is Thr or D-Thr; Xaa.sub.34 is Gln or D-Gln; Xaa.sub.35 is Arg or D-Arg; and Xaa.sub.36 is Tyr or D-Tyr; and wherein one D-isomer is present from among Xaa.sub.21, Xaa.sub.22, Xaa.sub.27, Xaa.sub.29, Xaa.sub.30, Xaa.sub.31, Xaa.sub.32, Xaa.sub.34, Xaa.sub.35 and Xaa.sub.36.
Claim: 2. The method of claim 1 wherein Xaa.sub.21 is D-Tyr.
Claim: 3. The method of claim 1 wherein the peptide has formula (a) and Xaa.sub.31 is D-Ile.
Claim: 4. The method of claim 1 wherein Xaa.sub.35 is D-Arg.
Claim: 5. The method of claim 1 wherein Xaa.sub.36 is D-Tyr.
Claim: 6. A peptide having the formula: H-Ala-Arg-Tyr-Xaa.sub.21 -Xaa.sub.22 -Ala-Leu-Arg-His-Xaa.sub.27 -Ile-Xaa.sub.29 -Xaa.sub.30 -Xaa.sub.31 -Xaa.sub.32 -Arg-Xaa.sub.34 -Xaa.sub.35 -Xaa.sub.36 -NH.sub.2, wherein Xaa.sub.21 is Tyr or D-Tyr, Xaa.sub.22 is Ser or D-Ser, Xaa.sub.27 is Tyr or D-Tyr, Xaa.sub.29 is Asn or D-Asn, Xaa.sub.30 is Leu or D-leu, Xaa.sub.31 is Ile or D-Ile, Xaa.sub.232 is Thr or D-Thr, Xaa.sub.34 is Gln or D-Gln, Xaa.sub.35 is Arg or D-Aeg, and Xaa.sub.36 is Tyr or D-Tyr; provided that one D-isomer is present from among Xaa.sub.21, Xaa.sub.22, Xaa.sub.27, Xaa.sub.29, Xaa.sub.30, Xaa.sub.31, Xaa.sub.32, Xaa.sub.34, Xaa.sub.35 and Xaa.sub.36.
Claim: 7. A peptide according to claim 6 wherein the peptide is selected from the group consisting of -NPY (18-36), -NPY (18-36), -NPY(18-36), -NPY(18-36) , -NPY(18-36) and -NPY (18-36) .
Claim: 8. A peptide according to claim 6 wherein Xaa.sub.21 is D-Tyr.
Claim: 9. A peptide according to claim 6 wherein Xaa.sub.35 is D-Arg.
Claim: 10. A peptide according to claim 6 wherein Xaa.sub.30 is D-Leu.
Claim: 11. A peptide according to claim 6 wherein Xaa.sub.30 is D-Ile.
Claim: 12. A pharmaceutical composition for lowering blood pressure comprising an effective amount of a peptide as set forth in claim 7 and a pharmaceutically acceptable liquid or solid carrier therefor.
Claim: 13. A peptide having the formula: H-Xaa.sub.18 -Arg-Tyr-Xaa.sub.21 -Xaa.sub.22 -Xaa.sub.23 -Leu-Arg-His-Xaa.sub.27 -Xaa.sub.28 -Xaa.sub.29 -Xaa.sub.30 -Xaa.sub.31 -Xaa.sub.32 -Arg-Xaa.sub.34 -Xaa.sub.35 -Xaa.sub.36 -NH.sub.2, wherein Xaa.sub.18 is Ala or Ser; Xaa.sub.21 is Tyr or D-Tyr; Xaa.sub.22 is Ser, D-Ser, Ala or D-Ala; Xaa.sub.23 is Ala or Ser; Xaa.sub.27 is Tyr or D-Tyr; Xaa.sub.28 is Ile or Leu; Xaa.sub.29 is Asn or D-Asn; Xaa.sub.30 is Leu or D-Leu; Xaa.sub.31 is Ile, D-Ile, Val or D-Val; Xaa.sub.32 is Thr or D-Thr; Xaa.sub.34 is Gln or D-Gln; Xaa.sub.35 is Arg or D-Arg; and Xaa.sub.36 is Tyr or D-Tyr; provided that one D-isomer is present from among Xaa.sub.21, Xaa.sub.22, Xaa.sub.27, Xaa.sub.29, Xaa.sub.30, Xaa.sub.31, Xaa.sub.32, Xaa.sub.34, Xaa.sub.35 and Xaa.sub.36.
Claim: 14. A peptide according to claim 13 wherein the peptide has the formula: H-Ser-Arg-Tyr-Xaa.sub.21 -Xaa.sub.22 -Ser-Leu-Arg-His-Xaa.sub.27 -Leu-Xaa.sub.29 -Xaa.sub.30 -Xaa.sub.31 -Xaa.sub.32 -Arg-Xaa.sub.34 -Xaa.sub.35 -Xaa.sub.36 -NH.sub.2.
Claim: 15. A peptide according to claim 14 wherein Xaa.sub.21 is D-Tyr.
Claim: 16. A peptide according to claim 14 wherein Xaa.sub.35 is D-Arg.
Claim: 17. A peptide according to claim 13 in the form of -NPY(18-36).
Claim: 18. A peptide according to claim 13 in the form of -NPY(18-36).
Claim: 19. A method according o claim 1 wherein an effective amount of -NPY(18-36in a pharmaceutically acceptable carrier is administered intravenously.
Current U.S. Class: 514/13; 514/12; 530/324; 530/326
Current International Class: A61K 3702; C07K 708; C07K 710
Patent References Cited: 4728726 March 1988 Rivier et al.
4764504 August 1988 Johnson et al.
5026685 June 1991 Boublik et al.
Other References: Rioux, F. et al., Peptides, 7(1):27-31, 1986.
Boublik, et al., "Synthesis and Hypertensive Activity of Neuropeptide Y Fragments and Analogs with Modified N-or C-Termini . . . " J. Med. Chem. 32: 597-601, 1989.
Boublik et al., "Neuropeptide .sup.18-36 -An NPY Fragment With Hypotensive Action in Vivo", Proc. 11th A.P.S., Ed. J. Rivier & G. Marshall 1990 pp. 317-318.
Boublik, et al., "Neuropeptide Y and neuropeptide Y.sub.8-36 : structural and biological characterization," Int. J. Peptide Protein Research, 33:11-15 (1989).
Scott, et al., "Distinction of NPY receptors in vitro and in vivo II. Differential effects of NPY and NPY-(18-36)," J. Med. Chem., 35(15):H174-H180 (1990).
Primary Examiner: Lee, Lester L.
Attorney, Agent or Firm: Fitch, Even, Tabin & Flannery
رقم الانضمام: edspgr.05328899
قاعدة البيانات: USPTO Patent Grants