Alpha-MSH analogue with therapeutic activity

A -NH2, CH3-C technology, applied in the field of peptide analogs of α-melanocyte-stimulating hormone (α-MSH), which can solve the problem of low protease sensitivity

Inactive Publication Date: 2014-01-08
ABBVIE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Structure-inducing probes force the parent peptide into a more ordered conformation based on intramolecular hydrogen bonds, whereby peptide chimeras (peptides attached to the probe) are less sensitive to proteases, as opposed to peptides in a random coil conformation

Method used

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  • Alpha-MSH analogue with therapeutic activity
  • Alpha-MSH analogue with therapeutic activity
  • Alpha-MSH analogue with therapeutic activity

Examples

Experimental program
Comparison scheme
Effect test

experiment approach 1

[0327] Inhibition of TNF-α production induced by LPS produced by human leukocytes in vitro

[0328] 20 mL of human blood was collected in a vacuum blood collection tube (vacutainer tube) containing EDTA. Peripheral blood mononuclear cells (PBMC) were isolated using Ficoll-Paque Plus from Amersham's Instruction 71-7167-00AD, 2002-06. PBMCs were counted using trypan blue solution (Sigma) and counted at 5 x 10 5 Cells / mL concentration PBMC were incubated in RPMI1640 (Applichem) supplemented with 10 mM hydroxyethylpiperazineethanesulfonic acid (Hepes) (Sigma), 2 mM L-glutamine (Sigma ), 0.1% bovine serum albumin (BSA) (Sigma), and 50 U / 50 μg / mL penicillin / streptomycin (Sigma). at 5% CO 2 Isolated PBMCs were incubated in 24-well flat bottom plates (Corning Incorporated) with culture medium, 10 ng LPS / mL (Sigma) and test compounds at 37°C in an atmosphere of , 95% air. After 18 hours, samples were centrifuged and assayed using Tumor Necrosis Factor Alpha [(h)TNF-α] from the Huma...

experiment approach 2

[0342] Inhibition of LPS-induced TNF-α production in rats

[0343] Experimental animals: Female Wistar rats (220-240g) were from Charles River (Charles River), Sulzfeld, Germany, and made to live in a temperature (22-24°C) and humidity (40-70%) controlled environment with a 12-hour Inside a room with a light-dark cycle (lighting from 6:00A.M. to 6:00P.M.). Rats were maintained on a standard rodent chow (with 140mmol / kg sodium, 275mmol / kg potassium and 23% protein, Altromin International, Lage, Germany) with free access to a water source.

[0344] Animal preparation: Under isoflurane-nitrous oxide anesthesia, durable medical grade polyethylene (Tygon) catheters were implanted into the abdominal aorta and inferior vena cava via the femoral artery and vein, respectively. Following implantation, animals were housed individually for 7-10 days until the day of the experiment.

[0345] Experimental procedure: Prior to the experiment, all rats were acclimated to the confinement cage...

experiment approach 3

[0354] Inhibition of neutrophil and eosinophil infiltration after LPS inhalation in rats

[0355] Male Sprague-Dawley rats from M&B A / S, DK-8680Ry, Denmark were used for all experiments. Rats were housed in type 3 standard cages in a temperature (22-24°C) and humidity (40-70%) controlled environment with a 12-hour light-dark cycle (from 6:00 A.M. to 6:00 A.M. :00P.M. for lighting). The feed was a special formula of autoclaved Altromin 1324 produced by Altromin Denmark (Chr. Pedersen A / S, 4100 Ringsted, Denmark). Feed and water were given ad libitum.

[0356] Rats were randomly assigned to experimental groups after acclimatization and test compounds were dosed intravenously at the beginning of LPS induction and again 8 hours after induction of LPS.

[0357]Rats in group 3 were anesthetized with 0.1 ml fentanyl / domacar / 100 g and dosed with the test compound intravenously. Immediately after dosing they were placed into a breathing chamber where they were sprayed with LPS solu...

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Abstract

The invention relates to an alpha-MSH analogue with therapeutic activity. The invention describes a peptide analogue of alpha-melanocyte stimulating hormone (alpha-MSH), which has improved efficacy when compared with natural alpha-MSH. Compared with alpha-MSH, the alpha-MSH analogue shows improved anti-inflammatory effect and improved capability of preventing ischaemia. The invention further discloses an application of the peptide to the preparation of pharmaceutical compositions, and the pharmaceutical compositions which are used for treatment or prevention of tissue diseases of one or more organs of mammal.

Description

[0001] This application is a divisional application of the Chinese patent application with the filing date of the original application being August 26, 2005, the application number being 200580051680.9, and the invention title being "therapeutically active α-MSH analogues". technical field [0002] The present invention relates to peptide analogs of alpha-melanocyte-stimulating hormone (α-MSH) which have improved efficacy compared to native alpha-MSH peptide. α-MSH analogues exhibit increased anti-inflammatory effects and increased efficacy in treating or preventing systemic injury, organ injury or cellular injury associated with ischemia or ischemia followed by vascular reperfusion compared to α-MSH ability. Background technique [0003] The natural peptide α-melanocytostimulating hormone (α-MSH) is well known as a natural agonist of type 1, type 3, type 4 and type 5 melanocortin (MC) receptors. MC receptors belong to the class of G-protein coupled receptors. All receptor...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K1/02C07K1/04C12P21/02
Inventor 托马斯·恩格尔布雷希特·诺克尔德·约纳森瑟伦·尼尔森约尔延·弗洛基尔比亚内迪尤·拉尔森
Owner ABBVIE INC
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