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SSTR1-selective analogs

a selective analog and analog technology, applied in the field of sstr1selective analogs, can solve the problems of intimal hyperplasia, invasive treatment of the arterial system, angioplasty or bypass surgery, etc., and achieve the effect of convenient labeling, effective use and high affinity

Inactive Publication Date: 2006-07-13
SALK INST FOR BIOLOGICAL STUDIES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes the creation of new peptides that can bind to a specific receptor in the body, called SSTR1. These peptides are more selective and have greater binding strength than previously known. They can be used to locate tumors that express SSTR1 receptors and can also be used as therapeutic agents to treat conditions mediated by SSTR1. The peptides can be labeled with radioactive materials and used for scintigraphy or radionuclide therapy. Overall, these peptides have improved properties for targeting and treating certain tumors.

Problems solved by technology

Interventional treatment to the arterial system, such as angioplasty or bypass surgery, can be damaging to the vessel wall.
However, if cell proliferation and matrix deposition continue, they lead to a pathological condition known as intimal hyperplasia (IH).
Apart from intravascular stents and anticoagulation, which appear effective in limiting restenosis in the short term, no other interventions have been successful in halting the development of IH; however, there is now evidence that SRIF may have an effect upon IH.
Clinical trials using angiopeptin to inhibit IH-causing restenosis, however, have been inconclusive.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of NαMeBoc-4aminomethylPhe(ipr)

[0045] The synthesis of L-N-MeBoc-N4-Cbz-(4-isopropylaminomethyl)phenylalanine, which is referred to by the shorthand nomenclature as Boc-NαMeIAmp(Z), is carried out as follows: L-Nα-Boc-(4-aminomethyl)phenylalanine (Boc-Amp) (15.3 g, 52 mmol) is dissolved in acetone (200 mL), and molecular sieves (6.0 g, 4 Å) are added to the solution in a 500 mL Parr hydrogenation vessel. The mixture is purged with N2 for 10 minutes; then Pd / C 10% (600 mg) is added. A reductive alkylation reaction occurs and is monitored by HPLC; it is carried out for about 26 hours. After filtration to remove the catalyst and molecular sieves and evaporation of the solvent, the desired intermediate L-Nα-Boc-(4-isopropylaminomethyl)phenylalanine is obtained as a viscous liquid.

[0046] The product is then Cbz-protected using benzyl chloroformate (Z-Cl, 8.6 mL, 60 mmol) in a mixture of THF / H2O (1:1,200 mL) at pH=9.5. A good yield of L-N-Boc-N4-Cbz-(4-isopropylaminomethyl)phe...

example 2

[0048] The somatostatin agonist des-AA1,2,5[D-Trp8, NαMeIAmp9, Tyr11]-SRIF having the structure: (cyclo)H-Cys-Lys-Phe-Phe-D-Trp-NαMeIAmp-Thr-Tyr-Thr-Ser-Cys-OH is synthesized by the solid phase methodology in a stepwise manner on a chloromethylated resin generally as described in Example 2 of the '499 patent. For the 9-position residue, the monomer synthesized in Example 1, i.e. Nα(Boc)Me-4-isopropylaminomethyl Phe(Z) is coupled into the chain. This synthesis creates the intermediate: Boc-Cys(Mob)-Lys(2-ClZ)-Phe-Phe-D-Trp-NαMeIAmp(Z)-Thr(Bzl)-Tyr(2BrZ)-Thr(Bzl)-Ser(Bzl)-Cys(Mob)-O-CH2-resin support.

[0049] Cleavage of the peptide from the resin and deprotection of the side chain protecting groups are performed in hydrofluoric acid(HF) (25 ml) in the presence of 10% of anisole and 5% of methylsulfide for 1.5 hours at 0° C. after 20 minutes at ambient temperature. After elimination of hydrofluoric acid under high vacuum, the resin-peptide is washed with anhydrous diethyl ether.

[0050]...

examples 2a and 2b

[0053] The synthesis described in Example 2 is repeated with one change; instead of using Nα(Boc)Me-4-isopropylaminomethyl Phe(Z) for the 9-position residue, Boc-4-isopropylamino Phe(Z), which is also referred to as Boc-IAmp(Z), is used. Cleavage, deprotection, cyclization and purification are carried out as in Example 2. A purified cyclic peptide having the formula: (cyclo)H-Cys-Lys-Phe-Phe-D-Trp-IAmp-Thr-Tyr-Thr-Ser-Cys-OH is obtained which appears to be greater than 98% pure on capillary zone electrophoresis. It is referred to as Peptide 2A. MS analysis shows a mass of 1501.5 Da which compares favorably with the calculated mass of 1500.66 Da.

[0054] A portion of the product Peptide 2A above is taken and subjected to iodination as well known in this art to iodinate the Tyr11. The iodinated compound is thereafter referred to as Peptide 2B. Radioactive iodination is instead used when desired to create a tracer. MS analysis shows a mass of 1627.5 Da which compares favorably to the ca...

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Abstract

Analogs of SRIF which are selective for SSTR1 in contrast to the other cloned SRIF receptors. These analogs are useful in determining the tissue and cellular expression of the receptor SSTR1 and its biological role in the endocrine, exocrine and nervous system, as well as in regulating tumor growth. SRIF analog peptides, such as des-AA1,2,5[D-Trp8, IAmp9, Tyr11]-SRIF and counterparts incorporating Cbm at the N-terminus, as well as radioiodinated versions thereof, inhibit the binding of a universal SRIF radioligand to the cloned human receptor SSTR1, but they do not bind with significant affinity to human SSTR2, SSTR3, SSTR4 or SSTR5. By incorporating an iodinated tyrosine in position-2 or in position-11 in these SSTR1-selective SRIF analogs, a labeled compound useful in drug-screening methods is provided. The N-terminus accommodates bulky moieties without loss of selectivity, and a carbamoyl moiety or a conjugating agent that will accept a radioactive nuclide or will link to a cytotoxin may be present at the N-terminus.

Description

[0001] This application is a division of U.S. Ser. No. 10 / 099,240, filed Mar. 15, 2002, which claims priority from U.S. Ser. No. 60 / 276,871, filed Mar. 16, 2001, the subject matter of both applications is incorporated herein by reference.[0002] This invention was made with Government support under Grant No. 5R01 DK50124 awarded by the National Institutes of Health. The Government has certain rights in this invention.[0003] 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 amino acid substitutions in such analogs and optional modification of the N-terminus that confer thereto receptor-selectivity and / or increased affinity to the receptor, to pharmaceutical compositions containing such peptides, to such peptides complexed with radioactive nuclides or conjugated to cytotoxins, to metho...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/31A61K51/08C07K14/655
CPCA61K51/088C07K14/6555A61K51/083
Inventor RIVIER, JEAN E.F.REUBI, JEAN CLAUDE
Owner SALK INST FOR BIOLOGICAL STUDIES
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