Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-07-31
2001-11-13
Davenport, Avis M. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S300000, C530S311000, C530S328000
Reexamination Certificate
active
06316414
ABSTRACT:
FIELD OF INVENTION
The present invention encompasses novel peptides that are agonists to somatostatin and the use of the agonists for treatment of cancer. The invention particularly relates to the design and synthesis of novel analogs of somatostatin incorporating &agr;, &agr;-dialkylated amino acids in a site specific manner. The invention encompasses methods for the generation of these peptides, compositions containing the peptides and the pharmacological applications of these peptides especially in the treatment and prevention of cancer.
BACKGROUND OF THE INVENTION
Somatostatin (SST) is a widely distributed peptide occurring in two forms SST-14 (with 14 amino acids) and SST-28 (with 28 amino acids). It was originally isolated from the hypothalamus and characterized by Guillemin et al. (U.S. Pat. No. 3,904,594) and is described in U.S. Pat. No. 3,904,594 (Sep. 9, 1975). Somatostatin is found in the gut, pancreas, in the nervous system, in the various exocrine and endocrine glands through the body and in most organs. In normal subjects somatostatin has a broad spectrum of biological activities. It participates in a large number of biological processes where it has the role of an inhibitory factor. It inhibits the release of insulin, prolactin, glucagon, gastrin, growth hormone, thyroid stimulating hormone, secretin and cholecystokinin. (S. Reichlin: Somatostatin, N.Eng. J. Med., 309,1495 and 1556, 1983.)
The mechanism of action of somatostatin is mediated by high affinity membrane associated receptors. Five somatostatin receptors (SSTR1-5) are known. (Reisine, T; Be11,G.I; Endocrine reviews, 1995, 16, 427-42.) All five receptors are heterogeneously distributed and pharmacologically distinct. Somatostatin receptors have been found to be over-expressed in a wide range of tumors, those arising in the brain (including meningioma, astrocytoma, neuroblastoma, hypophysial adenoma, paraganglioma, Merkel cell carcinoma, and gliomas), the digestive-pancreatic tract (including insulinoma, gluconoma, AUODoma, VIPoma, and colon carcinoma), lung, thyroid, mammary gland, prostate, lymphatic system (including both Hodgkin's and non-Hodgkin's lymphomas), and ovaries.
One of the most important effects of somatostatin are its growth-inhibiting ability and its capability to influence pathological cell growth. It is well known that it exerts an inhibitory effect on the growth of cancer cells both directly and by its antagonizing action on growth factors associated with malignant growth. (A. V. Schally: Cancer. Res., 48, 6977, (1988); Taylor, et. al., Biochem., Biophys. Res. Commun., 153, 81 (1988). It has been shown by recent investigations that somatostatin and some somatostatin analogues are capable of activating the tyrosine phosphatase enzyme which antagonizes the effect of tyrosine kinases playing a very important role in the tumorous transformation (A. V. Schally: Cancer Res. 48, 6977 (1988)). The importance of tyrosine kinases is supported by the fact that the majority of oncogenes code for tyrosine kinase and the major part of growth factor receptors is tyrosine kinase (Yarden et al.: Ann. Rev. Biochem. 57, 443 (1989)).
Native somatostatin has a very short or transient effect in vivo since it is rapidly inactivated by endo- and exopeptidases. A large number of novel analogues have been synthesized in order to increase its plasma half life and biological activity. Most of the active analogues contain a disulphide bond and a peptide chain shorter than the original one. The first cyclic hexapeptide showing the whole effects of somatostatin was synthesized by Veber et al. (Nature, 292, 55 (1981)). Newer and more effective cyclic hexa- and octapeptides have been synthesized which possess the whole spectrum of effects of somatostatin (Veber et al.; Life Sci. 34, 1371 (1984); Murphy et al.; Biochem. Biophys. Res. Commun. 132, 922 (1985); Cai et al.; Proc. Natl. Acad. Sci. USA 83, 1896 (1986)).
In spite of the high rates of over expression of somatostatin receptors on a variety of tumors, somatostatin analogues have not gained widespread clinical application for the control of cancer. Their current clinical application is primarily in the control of symptoms associated with metastatic carcinoid or VIP-secreting tumors. The somatostatin analogues have a wide therapeutic index and seem to be free of major side effects. Most of the side effects are gastrointestinal in nature and include minor nausea, bloating, diarrhea, constipation, or steatorrhea. Part of the reason for the restricted clinical use may be due to the need for long-term maintenance therapy, the consequent high cost of such therapy, and the variable effects observed in clinical settings.
Some somatostatin analogues, preparation of such analogues, and uses for such analogues are known in the prior art. Such analogues are used in the treatment of certain cancers and other conditions. One commercially available product, octreotide, D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-of (SEQ ID NO.: 1) (disulphide bridge between the Cys residue), manufactured by Sandoz, and sold under the trade name Sandostatin, is being used clinically to inhibit tumor growth and as a diagnostic agent to detect somatostain receptor expressing tumors. Of the five receptor sub-types, octreotide and other clinically used somatostatin analogs interact significantly with three of the receptor sub-types, SSTR2, SSTR3 and SSTRS. SSTR2 and SSTRS have recently been reported to mediate anti-proliferative effects of somatostatin on tumor cell growth, and may therefore mediate the effects of octreotide in humans.
A wide variety of somatostatin analogues have been developed. These include RC-160, a potent somatostatin analogue originally synthesized by a team at Tulane University headed by Andrew V. Schally (Cai R. Z., Szoke B., Lu E., Fu D., Redding T. W. and Schally A. V.: Synthesis and biological activity of highly potent octapeptide analogues of somatostatin. Proc Natl Acad Sci USA, 83:1896-1900, 1986). In recent studies conducted by Schally, among others, the effectiveness of RC-160 in inhibiting the growth of humor glioblastomas in vitro and in vivo has been demonstrated (Pinski J, Schally A V, Halmos G, Szepeshazi K and Groot K: Somatostatin analogues and bombesin/gastrin-releasing peptide antagonist RC-3095 inhibit the growth of human glioblastomas in vitro and in vivo. Cancer Res 54:5895-5901, 1994).
Recent patents that describe somatostatin analogs for treatment of cancer are following:
U.S. Pat. No. 6,025,372 (February 2000)
WO 0006185A2 (February 2000)
WO 9922735A1 (May 1999)
WO 9845285A1 (October 1998)
WO 9844921A1 (October 1998)
WO 9844922A1 (October 1998)
U.S. Pat. No. 5,753,618 (May 1998)
U.S. Pat. No. 5,597,894 (January 1997)
EP 0344297E 1 (May 1994)
JP 5124979A (May 1993)
U.S. Pat. No. 4,904,642 (February 1990)
The aim of the present invention is to synthesize novel somatostatin analogs showing a more advantageous and more selective biological action in comparison to that of known compounds. The invention is based on the use of &agr;, &agr;-dialkylated amino acids in the octapeptide analog of somatostatin at position 6. These amino acids are known for inducing conformational constraint. The design of conformationally constrained bioactive peptide derivatives has been one of the most widely used approaches for the development of peptide-based therapeutic agents. Non-standard amino acids with strong conformational preferences may be used to direct the course of polypeptide chain folding, by imposing local stereochemical constraints, in de novo approaches to peptide design. The conformational characteristics of &agr;, &agr;-dialkylated amino acids have been well studied. The incorporation of these amino acids restricts the rotation of &PHgr;, &PSgr; angles, within the molecule, thereby stabilizing a desired peptide conformation. The prototypic member of &agr;, &agr;-dialkylated aminoacids, &agr;-aminoisobutyric acid (Aib) or &agr;, &agr;-dimethylglycine has been shown to induce &bgr;-turn or helical conformation when incorporated in a peptide sequence (Pras
Burman Anand C.
Jaggi Manu
Mathur Archna
Mukherjee Rama
Prasad Sudhanand
Dabur Research Foundation
Davenport Avis M.
Ladas & Parry
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