Receptor-selective somatostatin analogs

• US 6,579,967 B1
• Filed: 06/29/2000
• Issued: 06/17/2003
• Est. Priority Date: 12/14/1999
• Status: Expired due to Term

• Current Assignee: Salk Institute for Biological Studies
• Original Assignee: Salk Institute for Biological Studies
• Inventors: Reubi, Jean Claude, Rivier, Jean E. F.
• Primary Examiner(s): Kunz, Gary
• Assistant Examiner(s): Landsman, Robert S.
• Application Number:
  US09/607,546
• Time in Patent Office: 1,083 Days
• Field of Search: 514/2, 514/9, 514/11, 530/300, 530/311, 930/160
• US Class Current: 530/311
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/04 for decreasing, blocking or antagonising the activity of the hypothalamic hormones
• CPC Class Codes: C07K 14/655 Somatostatins
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links
• CPC Class Codes: Y10S 930/16 Somatostatin; related peptides

Abstract

Analogs of SRIF which are selective for SSTR3 in contrast to the other cloned SRIF receptors. These analogs are useful in determining the tissue and cellular expression of the receptor SSTR3 and its biological role in the endocrine, exocrine and nervous system, as well as in regulating tumor growth. SRIF analog peptides, such as des-AA^{1,2,4,5,12,13}[N^βMeD-Agl⁸(2-naphthoyl) ]-SRIF and counterparts incorporating D-Cys³ and/or Tyr⁷, inhibit the binding of a universal SRIF radioligand to the cloned human receptor SSTR3, but they do not bind with significant affinity to human SSTR1, SSTR2, SSTR4 or SSTR5. By incorporating an iodinated tyrosine in position-2 or in position-11 in these SSTR3-selective SRIF analogs, a labeled compound useful in drug-screening methods is provided. Because the N-terminus accommodates bulky moieties without loss of selectivity, a cytotoxin or a complexing agent to accept a radioactive nuclide may be present at the N-terminus. Alternatively, the binding affinity may be improved without detriment to the selectivity by adding a carbamoyl moiety at the N-terminus and/or replacing Phe¹¹ with Aph or substituted Aph.

Claims

1. A cyclic somatostatin(SRIF) analog peptide which selectively binds the SRIF receptor SSTR3 in contrast to other SRIF receptors, wherein said peptide has the amino acid sequence (cyclo 3-14)Xaa₁-Xaa₂-Xaa₃-Phe-Xaa₇-D-Xaa₈-Lys-Thr-Xaa₁₁-Cys wherein Xaa₁ is des-Xaa, D-Ala, Ala, Cbm, L-Hor or an acyl group having up to 20 carbon atoms;

Xaa₂ is Tyr, D-Tyr, Gly or des-Xaa;

Xaa₃ is Cys or D-Cys;

Xaa₇ is an amino acid selected from the group consisting of (A)Phe, Tyr or N^β

MeAgl(Bz) wherein A is H, Cl, F, Br, NO₃, Me, OMe or NH(Q) where Q is H, Cbm or L-Hor;

D-Xaa₈ is an amino acid selected from the group consisting of D-Nal and N^β

MeD-Agl(Np); and

Xaa₁₁ is Phe, Aph(X) or Tyr with X being H, Ac or Cbm;

provided that either Xaa₇ is N^β

MeAgl(Bz) or D-Xaa₈ is N^β

MeD-Agl(Np).

2. The peptide according to claim 1 wherein Xaa₁ and Xaa₂ are des-Xaa.

3. The peptide according to claim 1 wherein D-Xaa₈ is N^β

MeD-Agl(Np) and Xaa₇ is (A)Phe or Tyr.

4. The peptide according to claim 3 wherein Xaa₃ is D-Cys.

5. The peptide according to claim 3 wherein D-Xaa₈ is N^β

MeD-Agl(2-naphthoyl).

6. The peptide according to claim 5 wherein Xaa₇ is Tyr.

7. The peptide according to claim 6 wherein Xaa₃ is D-Cys.

8. The peptide according to claim 1 wherein Xaa₇ is N^β

MeAgl(Bz) and D-Xaa₈ is D-2Nal.

9. The peptide according to claim 1 wherein there is present at the N-terminus a complexing agent capable of joining thereto a radioactive nuclide or a conjugating agent for linking to a cytotoxin.

10. The peptide according to claim 1 having the amino acid sequence:

(cyclo 3-14)Xaa₁-Xaa₂-Xaa₃-Phe-Xaa₇-D-Xaa₈-Lys-Thr-Xaa₁₁-Cys wherein Xaa₁ is Cbm;

Xaa₂ is Tyr, D-Tyr or des-Xaa;

Xaa₃ is Cys or D-Cys;

Xaa₇ is (A)Phe or Tyr; and

D-Xaa₈ is N^β

MeD-Agl(Np).

11. The peptide according to claim 1 having the amino acid sequence:

(cyclo 3-14)Xaa₁-D-Cys-Phe-Xaa₇-N^β

MeD-Agl(2-naphthoyl)-Lys-Thr-Xaa₁₁-Cys, wherein Xaa₁ is Cbm or des-Xaa;

Xaa₇ is Phe or Tyr and Xaa₁₁ is Phe or Aph(X).

12. A pharmaceutical composition comprising a mixture of the peptide according to claim 1 and at least one pharmaceutically acceptable carrier.

13. A cyclic somatostatin (SRIF) analog peptide having specific affinity for the SRIF receptor SSTR3 greater than its affinity for other SRIF receptors, wherein said peptide has an amino acid sequence at least 8 residues in length, contains a Cys-Cys disulfide bond with a sequence of at least 6 residues located between said Cys residues as a ring, and contains Phe-Xaa₇-D-Xaa₈-Lys-Thr adjacent to the Cys residue near the N-terminus, wherein said analog comprises either N^β

MeD-Agl(2-naphthoyl) at position D-Xaa₈ and Phe or Tyr at position Xaa₇ or N^β

Me-Agl(2-benzoyl) at position Xaa₇ and D-2Nal at position D-Xaa₈.

14. The peptide according to claim 13 wherein D-Xaa₈ is N^β

MeD-Agl(2-naphthoyl) and Cbm is present at the N-terminus.