crhr2 peptide agonists and uses thereof

A technology for agonists and hormones, which can be used in applications, hormone peptides, specific peptides, etc., and can solve problems such as relative binding affinity, receptor activation degree, and selectivity differences.

Inactive Publication Date: 2011-12-07
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these receptors share a high degree of sequence homology, different members of the CRH peptide family exhibit marked differences in their relative binding affinities, extent of receptor activation, and selectivity for these two receptors

Method used

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  • crhr2 peptide agonists and uses thereof
  • crhr2 peptide agonists and uses thereof
  • crhr2 peptide agonists and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0168] Example 1: Synthesis and purification of peptides

[0169] The peptide of SEQ ID NO: 29 was prepared by solid-phase peptide synthesis on a Rainin Symphony multi-channel peptide synthesizer (SMPS-110 model) using software version 3.3.0. Resin for peptide amide synthesis (NovaSyn TGR , 440mg, approximately 0.1mmol, degree of substitution 0.23mmol / g, batch number A33379) is a composite material of polyethylene glycol and polystyrene functionalized with acid-labile modified Rink amide linker.

[0170] The amino acid used for synthesis contains the Nα-9-fluorenylmethoxycarbonyl (Fmoc) protecting group at the C-terminus and the following side chain protecting group: arginine (2,2,4,6,7-pentamethyldi Hydrobenzofuran-5-sulfonyl, pbf), aspartic acid (tert-butoxy, OtBu), asparagine (trityl, Trt), glutamine (Trt), cysteine ​​( Trt), histidine (Trt), lysine (tert-butoxycarbonyl, Boc), serine (tert-butyl, tBu) and threonine (tBu).

[0171] By mixing N-methylpyrrolidone (NMP) p...

example 2

[0175] Example 2: Coupling of peptides with N-ethylmaleimide

[0176] The N-ethylmaleimide end-capping reaction on cysteine ​​residues shown in Scheme 1 was realized according to the following conditions.

[0177] plan 1

[0178]

[0179] In a 2.5 mL polypropylene vial, 2.0 mg of the peptide of the invention was dissolved in 1.0 mL of water. Then 20 microliters of 0.1M aqueous N-ethylmaleimide solution was added immediately. The reaction mixture was stirred gently at room temperature for 2 hours. The reaction mixture was purified on a Summit APS (Dionex, CA, U.S.A.) HPLC equipped with a 300 Angstrom pore size Vydac C18 column (10 x 250 mm; Grace Davison, IL, U.S.A.) using the protocol shown in Table 6 below. Final fractions were collected, analyzed by HPLC, and pure fractions were pooled and lyophilized.

[0180] Table 6

[0181] Column:

example 3

[0182] Example 3: Coupling of Peptides to Iodoacetamide-PEG

[0183] Iodoacetamide-PEG, a 20 kDa polyethylene glycol linear chain with iodoacetamide termini, is present in limiting amounts with the peptide of SEQ ID NO: 29 at slightly alkaline pH, resulting in cysteine ​​modifications such as Specific reactions shown in Scheme 2. Cysteine ​​thiols serve as selective attachment sites for iodoacetamide-PEG. The resulting derivatized α-thiol acetamide linkage is achiral.

[0184] Scenario 2

[0185]

[0186] To a 15 mL Erlenmeyer flask was added 25 mg (5.68 mmol, 1.0 equiv) of the peptide of SEQ ID NO: 1. To the above Erlenmeyer flask was added 140 mg (6.82 mmol, 1.2 equivalents, 95% active) of PEG-20 iodoacetamide produced by Nippon, Oil and Fat (NOF) Corp. (Lot No. M77592). Add 10 mL of water and vortex the solution until all solids are dissolved. To this cloudy solution was added 50 mL of pyridine having a solution pH of about 8.91. After 2 hours, a 20 mL aliquot wa...

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Abstract

The present invention relates to novel peptides that are selective corticotropin releasing hormone receptor type 2 (CRHR2) agonists and compositions thereof for the treatment, amelioration or inhibition of cardiovascular conditions, including but not limited to heart failure. The novel peptide agonists preferably comprise modifications that include pegylated peptides. Furthermore, the present invention also relates to methods for the treatment and prevention of a disease or disorder related to CRHR2 activity.

Description

[0001] Cross references to related patent applications [0002] This patent application claims priority to US Provisional Patent Application Serial No. 61 / 111,233, filed November 4, 2008, and US Provisional Patent Application Serial No. 61 / 178,890, filed May 15, 2009. technical field [0003] The present invention relates generally to peptides useful as stresscopin mimetics for the treatment of medical indications mediated by corticotropin releasing hormone receptor 2 activity, constructs for peptide delivery, pharmaceutical combinations comprising them and methods of treating a subject diagnosed with a corticotropin-releasing hormone receptor 2-mediated disease, disorder, or medical condition. Background technique [0004] Heart failure is a common cardiovascular disorder and has reached epidemic proportions in the United States and Europe (Remme et al., Eur. Heart J., 2001, Vol. 22, pp. 1527-1560). In the United States alone, nearly one million people are hospitalized eac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/575C12N15/12C07K16/18A61K38/22
CPCA61K38/00C07K14/57509A61P3/00A61P43/00A61P9/00A61P9/10A61P3/10C07K14/575C12N15/11A61K38/22
Inventor R·V·斯万森N·P·尚克利V·莫尔诺P·金戈
Owner JANSSEN PHARMA NV
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