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Novel alanyl-amino peptidase inhibitors for functionally influencing different cells and treating immunological, inflammatory, neuronal, and other diseases

A technology of compounds and general formulas, applied in the fields of extracellular fluid diseases, nervous system diseases, anti-inflammatory agents, etc.

Inactive Publication Date: 2007-01-17
INSTITUT FUR MEDIZINTECH MAGDEBURG IMTM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Inhibition of alanyl aminopeptidase and similar enzymes, respectively, but especially the combined inhibition of these peptidases with dipeptidyl peptidase IV and similar enzymes leads to a strong inhibition of DNA synthesis and, consequently, to a decrease in cell proliferation in immune cells Strong inhibition and lead to changes in cytokine production, especially induction of TGF-β1 leading to potent immune regulation (Published International Patent Application No. WO 01 / 89569 A1; Published International Patent Application No. WO02 / 053170 A3)

Method used

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  • Novel alanyl-amino peptidase inhibitors for functionally influencing different cells and treating immunological, inflammatory, neuronal, and other diseases
  • Novel alanyl-amino peptidase inhibitors for functionally influencing different cells and treating immunological, inflammatory, neuronal, and other diseases
  • Novel alanyl-amino peptidase inhibitors for functionally influencing different cells and treating immunological, inflammatory, neuronal, and other diseases

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Experimental program
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Effect test

Embodiment 1

[0064] Inhibition Characteristics of New Inhibitors of Alanyl Aminopeptidase

[0065] In Tables 1 to 14 below, new inhibitors are summarized, for which the inventors have shown that these substances are capable of inhibiting alanyl aminopeptidase and enzymes with similar effects in enzymatic activity. Inhibition characteristics were measured as IC-50 values ​​or ID50 values ​​(the latter marked with "*") for the enzymes in question. Via fluorescent substrate / product (Ala) 2 -Rhodamine 110 to measure enzyme activity.

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Embodiment 2

[0218] Combined inhibition of alanyl aminopeptidase and similar enzymes and dipeptidyl peptidase IV and similar enzymes against experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of multiple sclerosis treatment effect

[0219] The disease EAE was induced by daily injection of PLP139-151 (myelin antigen protein lipoprotein peptide 139-151) to SJL / J mice (n=10). Following disease onset, which is day 11 after immunization, therapeutic intervention was performed by intraperitoneal injection of 1 mg of each peptidase inhibitor on the first day and further 0.5 mg of each inhibitor every other day. Disease scores are defined by clearly varying degrees of paralysis [vD1]. Healthy animals have a disease score of 0. Actinonine is used as alanyl aminopeptidase inhibitor, Lys[Z(NO 2 )] pyrrolidine anhydride (pyrrolidide) is used as a dipeptidyl peptidase IV inhibitor. Treatment was performed 46 days after immunization. The results are shown in figure 1 middle. ...

Embodiment 3

[0221] Combined inhibition of alanyl aminopeptidase and similar enzymes and dipeptidyl peptidase IV and similar enzymes against dextran sulfate-induced colitis (an animal model of chronic inflammatory small bowel disease) in mice treatment effect

[0222] Primary colon-associated inflammation (a disease equivalent to human ulcerative colitis) was induced in 8-week-old female Balb / c mice by administration of 3% dextran sodium sulfate dissolved in drinking water. After three days, all animals showed obvious symptoms typical of the disease. Peptidase inhibitors (or phosphate-buffered saline as placebo) were administered intraperitoneally from day 5 for three consecutive days. The extent of disease is determined according to a known rating system (score). When determining the score, the following parameters were considered: consistency of the stool (solid = 0 points (pts.); mushy = 2 pts.; liquid / as diarrhea = 4 pts.); detection of blood in the stool (no blood = 0 pts. ; occult...

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Abstract

The invention relates to medicinally used substances which specifically inhibit peptidases splitting ala-p-nitroanilide. The invention further relates to the use of at least one such substance or at least one pharmaceutical or cosmetic composition containing such a substance for preventing and treating diseases, especially diseases with an overshooting immune response (autoimmune diseases, allergies, and transplant rejections), other chronic inflammatory diseases, neuronal diseases, brain damages, skin diseases (acne and psoriasis, among others), tumor diseases, and special viral infections (including SARS).

Description

Background technique [0001] Aminopeptidase N (APN, CD13, EC 3.4.11.2) belongs to the (ubiquitous) group of alanyl aminopeptidases produced mainly as type II membrane proteins, as well as cytosolic soluble alanyl aminopeptidases (EC 3.4. 11.14; Puromycin-sensitive aminopeptidase, aminopeptidase PS, encephaline-degrading aminopeptidase). Both peptidases act in a metal-dependent manner and catalyze the hydrolysis of the peptide bond following the N-terminal amino acid of the oligopeptide, in the case of APN, preferably the N-terminal alanine (A.J. Barrett et al.: Handbook of Proteolytic Enzymes, Academic Press , 1988). All inhibitors of aminopeptidase N also inhibit cytosolic alanyl aminopeptidase, although there are specific inhibitors of cytosolic aminopeptidase (M. Komodo et al.; Bioorg. and Med. Chem. 9, 121 (2001) ). [0002] For both groups of enzymes, important biological functions were demonstrated in different cellular systems. This effect on the immune system (U.Len...

Claims

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Application Information

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IPC IPC(8): A61K31/00A61K31/4015C07C259/06C07C317/44C07C325/02C07C327/48C07D207/46C07D221/14C07D233/90C07D241/52C07D253/06C07D257/04C07D261/20C07D307/46C07D323/00C07D333/36C07D339/08C07D405/06C07D405/12C07D413/12C07D413/14C07D487/04C07D513/04C07F9/53
CPCC07C317/44C07D413/14C07C327/48C07D339/08C07D261/20C07D333/36C07D405/12C07D513/04C07D221/14C07D307/46C07D413/12C07C325/02C07D257/04C07F9/5333C07D405/06C07D207/46C07D253/06C07C2101/14C07D323/00C07C259/06C07D487/04C07D241/52C07D233/90C07C2101/10A61P1/00A61P7/00A61P9/08A61P9/10A61P11/06A61P11/08A61P13/12A61P17/00A61P17/02A61P17/06A61P25/00A61P25/16A61P25/28A61P29/00A61P35/00A61P37/02A61P37/08A61P43/00C07C2601/10C07C2601/14
Inventor S·安佐格U·班克K·诺德霍夫M·塔格尔F·斯蒂戈欧
Owner INSTITUT FUR MEDIZINTECH MAGDEBURG IMTM
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