Receptor-selective somatostatin analogs

Details Receptor-selective somatostatin analogs Receptor-selective somatostatin analogs

2000-06-29

2003-06-17

Kunz, Gary (Department: 1647)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Somatostatin ; related peptides

C530S300000, C930S160000

Reexamination Certificate

active

06579967

ABSTRACT:

This invention is directed to peptides related to somatostatin and to methods for pharmaceutical treatment of mammals using such peptides. More specifically, the invention relates to shortened receptor-selective somatostatin analogs and the inclusion of an amino acid substitution in such analogs that confers receptor-selectivity thereto, to pharmaceutical compositions containing such peptides, to such peptides complexed with radioactive nuclides or conjugated to cytotoxins, to methods of diagnostic and therapeutic treatment of mammals using such peptides, particularly peptides that are chelated or otherwise labelled, and to methods for screening for more effective drugs using such peptides.
BACKGROUND OF THE INVENTION
The cyclic tetradecapeptide somatostatin-14 (SRIF) was originally isolated from the hypothalamus and characterized as a physiological inhibitor of growth hormone release from the anterior pituitary. It was characterized by Guillemin et al. and is described in U.S. Pat. No. 3,904,594 (Sep. 9, 1975). This tetradecapeptide has a bridging or cyclizing bond between the sulfhydryl groups of the two cysteinyl amino acid residues in the 3- and 14-positions. SRIF was found to also regulate insulin, glucagon and amylase secretion from the pancreas, and gastric acid release in the stomach, e.g. it inhibits the effects of pentagastrin and histamine on the gastric mucosa. SRIF is also expressed in intrahypothalamic regions of the brain and has a role in the regulation of locomotor activity and cognitive functions. SRIF is localized throughout the central nervous system, where it acts as a neurotransmitter. In the central nervous system, SRIF has been shown to both positively and negatively regulate neuronal firing, to affect the release of other neurotransmitters, and to modulate motor activity and cognitive processes.
Somatostatin and many analogs of somatostatin exhibit activity in respect to the inhibition of growth hormone (GH) secretion from cultured, dispersed rat anterior pituitary cells in vitro; they also inhibit GH, insulin and glucagon secretion in vivo in the rat and in other mammals. One such analog is [D-Trp
8
]-SRIF which has the amino acid sequence: (cyclo 3-14)H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH, which is disclosed in U.S. Pat. No. 4,372,884 (Feb. 8, 1983). Somatostatin has also been found to inhibit the secretion of gastrin and secretin by acting directly upon the secretory elements of the stomach and pancreas, respectively, and somatostatin is being sold commercially in Europe for the treatment of ulcer patients. The powerful inhibitory effects of somatostatin on the secretion not only of GH but also of insulin and glucagon have led to studies of a possible role of somatostatin in the management or treatment of juvenile diabetes and have proved useful in studying the physiological and pathological effects of these hormones on human metabolism. SRIF is also known to inhibit the growth of certain tumors.
L. Pradayrol, et al. in
FEBS Letters
109, January 1980, pages 55-58, reported the isolation and characterization of somatostatin-28 (SRIF-28) from porcine upper small intestine. SRIF-28 is an N-terminally extended version of SRIF which has an additional 14 amino acid residues and which shows some increased potency when administered in vivo.
SRIF affects multiple cellular processes. Studies have shown that SRIF is an inhibitory regulator of adenylyl cyclase in different tissues. SRIF also regulates the conductance of ionic channels, including both K
+
and Ca
2+
channels. These actions of SRIF are mediated via pertussis toxin-sensitive guanine nucleotide-binding proteins. SRIF also regulates the activity of tyrosine phosphatases, the Na
+
/H
+
antiport, and cellular proliferation through pertussis toxin-insensitive mechanisms.
SRIF induces its biological effects by interacting with a family of membrane-bound structurally similar receptors. Five SRIF receptors have been cloned and are referred to as SSTR1-5. Human SSTR1, mouse SSTR2 and mouse SSTR3 are described in Raynor et al.,
Molecular Pharmacology
, 43, 838-844 (1993), and all five human SRIF receptors are now available for research purposes. Human SSTR1, 2 and 3 are also disclosed in U.S. Pat. No. 5,436,155 (Jul. 25, 1995). Additional SRIF receptors are disclosed in U.S. Pat. No. 5,668,006 (Sep. 16, 1997) and 5,929,209 (Jul. 27, 1999). All five receptors bind SRIF and SRIF-28 with high affinity. Selective agonists at SSTR2 and SSTR5 have been identified and used to reveal distinct functions of these receptors. These two receptors are believed to be the predominant subtypes in peripheral tissues. SSTR2 is believed to mediate the inhibition of growth hormone, glucagon and gastric acid secretion. In contrast, SSTR5 appears to be primarily involved in the control of insulin and amylase release. SSTR3 is found in cortex tissue, in the pituitary and in ademoma tumor tissue; it is believed to mediate inhibition of gastric smooth muscle contraction upon binding by SRIF. These findings indicate that different receptor subtypes mediate distinct functions of SRIF in the body.
There are different types of tissues in the human body that express somatostatin receptors including: (1) the gastrointestinal tract, likely including the mucosa and smooth muscle, (2) the peripheral nervous system, (3) the endocrine system, (4) the vascular system and (5) lymphoid tissue, where the receptors are preferentially located in germinal centers. In all these cases, somatostatin binding is of high affinity and specific for bioactive somatostatin analogs.
Somatostatin receptors are also expressed in pathological states, particularly in neuroendocrine tumors of the gastrointestinal tract. Most human tumors originating from the somatostatin target tissue have conserved their somatostatin receptors. It was first observed in growth hormone producing adenomas and TSH-producing adenomas; about one-half of endocrine inactive adenomas display somatostatin receptors. Ninety percent of the cardinoids and a majority of islet-cell carcinomas, including their metastasis, usually have a high density of somatostatin receptors. However, only 10 percent of colorectal carcinomas and none of the exocrine pancreatic carcinomas contain somatostatin receptors. The somatostatin receptors in tumors can be identified using in vitro binding methods or using in vivo imaging techniques; the latter allow the precise localization of the tumors and their metastasis in the patients. Because somatostatin receptors in gastroenteropancreatic tumors are functional, their identification can be used to assess the therapeutic efficacy of an analog to inhibit excessive hormone release in the patients.
A cyclic SRIF analog, variously termed SMS-201-995 and Octreotide, i.e. D-Phe-c[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-ol is being used clinically to inhibit certain tumor growth; analogs complexed with
111
In or the like are also used as diagnostic agents to detect SRIF receptors expressed in cancers. Two similar octapeptide analogs having 6-membered rings, i.e. Lanreotide and Vapreotide, have also been developed, see Smith-Jones et al.,
Endocrinology
, 140, 5136-5148 (1999). A number of versions of these somatostatin analogs have been developed for use in radioimaging or as radiopharmaceuticals in radionuclide therapy. For radioimaging, for example, labeling with
123
I can be used as disclosed in U.K. Patent Application 8927255.3 and as described in Bakker et al., 1991
, J. Nucl. Med
., 32:1184-1189. Proteins have been previously radiolabeled through the use of chelating agents, and there are various examples of complexing somatostatin analogs with
99
Tc,
90
Y or
111
In, see U.S. Pat. Nos. 5,620,675 and 5,716,596. A variety of complexing agents have been used including DTPA (Dirgolini, et al.,
European Journal of Nuclear Medicine
, 23:1388-1399, October 1996); (Stabin, et al.,
J. Nuc. Med
., 38:1919-1922, December 1997); (Vallabhajosula, et al.,
J. Nuc. Med
., 37:1016-1022, June 1996); DOTA (De Jong, et

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