Conformationally constrained backbone cyclized somatostatin analogs

• US 7,060,679 B2
• Filed: 08/12/2004
• Issued: 06/13/2006
• Est. Priority Date: 06/19/1998
• Status: Expired due to Term

• Current Assignee: Strongbridge Ireland Limited (Novo Nordisk A/S)
• Original Assignee: DeveloGen Israel Ltd.
• Inventors: Gellerman, Gary, Hornik, Vered, Afargan, Michel M.
• Primary Examiner(s): Campbell, Bruce R.
• Assistant Examiner(s): AUDET, MAURY A
• Application Number:
  US10/916,522
• Publication Number:
  US 20050043226A1
• Time in Patent Office: 670 Days
• Field of Search: 514/9
• US Class Current: 514/7.3
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/6555 at least 1 amino acid in D-form
• CPC Class Codes: G01R 31/31816 Soft error testing; Soft error rate evaluation; Single event testing
• CPC Class Codes: G01R 31/318541 Scan latches or cell details

Abstract

Methods of use of pharmaceutical compositions and novel peptides which are conformationally constrained backbone cyclized somatostatin analogs, having somatostatin receptor subtype selectivity, are disclosed. These patterns or receptor subtype selectivity provide compounds having improved therapeutic utility. Methods for synthesizing the somatostatin analogs and for screening of the somatostatin analogs are also disclosed. Furthermore, pharmaceutical compositions comprising somatostatin analogs are disclosed.

Claims

1. A method for treating disorders selected from the group consisting of cancers, diabetes, diabetic-associated complications, endocrine disorders, gastrointestinal disorders, and pancreatitis, comprising administering to a mammal having one of such disorders and in need of treatment thereof a pharmaceutical composition that includes a therapeutically effective amount of a backbone cyclized somatostatin analog comprising a peptide sequence of four to twelve amino acids that incorporates at least one building unit, said building unit containing one nitrogen atom of the peptide backbone connected to a bridging group comprising an amide, thioether, thioester, or disulfide, wherein the at least one building unit is connected via the bridging group to form a cyclic structure with a moiety selected from the group consisting of a second building unit, the side chain of an amino acid residue of the sequence or the N-terminal amino acid residue, wherein the sequence includes a non-cyclized chain of 4, 5 or 6 amino acids.

2. The method according to claim 1, wherein the backbone cyclized somatostatin analog is selective for one somatostatin receptor subtype.

3. The method according to claim 1, wherein the backbone cyclized somatostatin analog is selective for two somatostatin receptor subtypes.

4. The method according to claim 1, wherein the backbone cyclized somatostatin analog is represented by the structure of the general formula 7:

5. The method according to claim 1, wherein the backbone cyclized somatostatin analog is represented by the structure of the general formula 8:

6. The method according to claim 1, wherein the backbone cyclized somatostatin analog is represented by the structure of the general formula 9:

7. The method according to claim 1, wherein the backbone cyclized somatostatin analog is represented by the structure of the general formula 13:

8. The method according to claim 1, wherein the backbone cyclized somatostatin analog is represented by the structure of the general formula 14:

9. The method according to claim 1, wherein the backbone cyclized somatostatin analog is represented by the structure of the general formula 15:

10. The method according to claim 1, wherein the backbone cyclized somatostatin analog is

21. The method according to claim 1, wherein the diabetes is Non Insulin Dependent Diabetes Mellitus (NIDDM).

11. A method for diagnosing cancer comprising administration of a backbone cyclized somatostatin analog to a mammal in an amount effective to identify cancer in the mammal, with the analog comprising a peptide sequence of four to twelve amino acids that incorporates at least one building unit, said building unit containing one nitrogen atom of the peptide backbone connected to a bridging group comprising an amide, thioether, thioester, or disulfide, wherein the at least one building unit is connected via the bridging group to form a cyclic structure with a moiety selected from the group consisting of a second building unit, the side chain of an amino acid residue of the sequence or the N-terminal amino acid residue, wherein the sequence includes a non-cyclized chain of 4, 5 or 6 amino acids.

12. The method according to claim 11, wherein the backbone cyclized somatostatin analog is used for imaging the existence of metastases.

13. The method according to claim 11, wherein the backbone cyclized somatostatin analog is labeled with a detectable probe.

14. The method according to claim 11, wherein the backbone cyclized somatostatin analog is represented by the structure of the general formula 7:

general formula 7;

15. The method according to claim 11, wherein the backbone cyclized somatostatin analog is represented by the structure of the general formula 8:

16. The method according to claim 11, wherein the backbone cyclized somatostatin analog is represented by the structure of the general formula 9:

17. The method according to claim 11, wherein the backbone cyclized somatostatin analog is represented by the structure of the general formula 13:

18. The method according to claim 11, wherein the backbone cyclized somatostatin analog is represented by the structure of the general formula 14:

19. The method according to claim 11, wherein the backbone cyclized somatostatin analog is represented by the structure of the general formula 15:

20. The method according to claim 11, wherein the backbone cyclized somatostatin analog is

22. A method of identifying a potential carcinoid drug, comprising

contacting a cancer cell with a backbone cyclized somatostatin analog comprising a peptide sequence of four to twelve amino acids that incorporates at least one building unit, said building unit containing one nitrogen atom of the peptide backbone connected to a bridging group comprising an amide, thioether, thioester, or disulfide, wherein the at least one building unit is connected via the bridging group to form a cyclic structure with a moiety selected from the group consisting of a second building unit, the side chain of an amino acid residue of the sequence or the N-terminal amino acid residue, wherein the sequence includes a non-cyclized chain of 4, 5 or 6 amino acids;

and

measuring a change in the level or activity of a cellular target.

23. The method of claim 22, comprising measuring cell growth, level of cyclic adenosine monophosphate (cAMP), growth hormone and chromogranin A secretion;

or tyrosine phosphatase activity.