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Novel dipeptidyl peptidase IV inhibitors used for functionally influencing different cells and treating immunological, infammatory, neuronal, and other diseases

A technology based on residues and basic structures, applied in smaller molecules and easy fields, can solve problems such as changes in cell proliferation and cytokines

Inactive Publication Date: 2007-01-03
INSTITUT FUR MEDIZINTECH MAGDEBURG IMTM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Separate inhibition of dipeptidyl peptidase IV and similar peptidases, but especially combined inhibition of dipeptidyl peptidase IV and alanyl aminopeptidase (EC 3.4.11.2 and EC 3.4.11.14) resulted in DNA synthesis , and thus, lead to a strong inhibition of cell proliferation in immune cells as well as to changes in cytokine production, especially to the induction of TGF-β1 that is effective in immunoregulation (Published International Patent Application No. WO 01 / 89569 D1; Published International Patent Application No. WO 02 / 053170 A3)

Method used

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  • Novel dipeptidyl peptidase IV inhibitors used for functionally influencing different cells and treating immunological, infammatory, neuronal, and other diseases
  • Novel dipeptidyl peptidase IV inhibitors used for functionally influencing different cells and treating immunological, infammatory, neuronal, and other diseases
  • Novel dipeptidyl peptidase IV inhibitors used for functionally influencing different cells and treating immunological, infammatory, neuronal, and other diseases

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Inhibitory characteristics of new inhibitors of dipeptidyl peptidase IV

[0066] In the following tables (Tables 1 to 14) new inhibitors are summarized, for which the inventors have shown that these substances are capable of inhibiting dipeptidyl peptidase IV and enzymes with similar effects in enzymatic activity. Inhibition characteristics were measured as IC-50 values ​​or ID 50 values ​​(the latter marked with "*") for the enzymes in question. Via fluorescent substrate (Ala-Pro) 2 -Rhodamine 110 to measure enzyme activity.

[0067] Table 1

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[0069] Table 2

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[0092] Table 4

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Embodiment 2

[0200] Combined inhibition of dipeptidyl peptidase IV and similarly acting enzymes and alanyl aminopeptidase and similarly acting enzymes against experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of multiple sclerosis treatment effect

[0201] 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 a further injection of 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 result...

Embodiment 3

[0203] Combined inhibition of dipeptidyl peptidase IV and similarly acting enzymes and alanyl aminopeptidase and similarly acting enzymes against dextran sulfate-induced colitis (an animal model of chronic inflammatory disease of the small intestine) in mice treatment effect

[0204] 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...

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Abstract

The invention relates to medicinally used substances which specifically inhibit peptidases splitting Gly-Pro-p-nitroanilide. The invention further relates to the use of at least one such substance or at least one pharmaceutical or cosmetic composition containing at least one such substance for preventing or treating diseases, particularly 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 of the invention [0001] Dipeptidyl peptidase IV (DPIV; CD26; EC 3.4.14.5) is a ubiquitous serine protease that specifically catalyzes the hydrolysis of peptides following a proline or alanine at the second position of the plus end. The gene family of DPIV with enzymatic activity also includes, inter alia, DP 8, DP 9 and FAP / seprase (T. Chen et al.: Adv. Exp. Med. Biol. 524, 79, 2003). A substrate similar in specificity to DPIV was shown by Attractin (mahagony protein) (J.S. Duke-Cohan et al.: J. Immunol. 156, 1714, 1996). The enzyme is also inhibited by an inhibitor effective against DPIV. [0002] For dipeptidyl peptidase IV, attractin and FAP, important biological functions were demonstrated in different cell systems. This is for the immune system (U.Lendeckel et al: Intern.J.Mol.Med.4,17,1999; T.Khne et al:Intern.J.Mol.Med.4,3,1999; I.De Meester et al:Advanc .Exp.Med.Biol.524,3,2002; Published International Patent Application WO 01 / 89569 D1; Published Interna...

Claims

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Application Information

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IPC IPC(8): A61K31/55C07D405/12C07C229/34C07C235/56C07C243/28C07C251/80C07C251/86C07C255/61C07C259/14C07C271/28C07C311/08C07C311/19C07C311/29C07C323/60C07C327/48C07D205/08C07D213/82C07D225/02C07D401/12C07D417/12C07F9/6506
CPCC07C327/48C07C235/56C07C2103/74C07D205/08C07D405/12C07C311/08C07F9/65061C07C255/61C07C311/29C07C323/60C07D225/02C07D401/12C04B35/632C07C243/28C07D417/12C07C271/28C07C251/80C07C259/14C07C229/34C07D213/82C07C2101/10C07C251/86C07C311/19A61P1/04A61P11/06A61P25/00A61P29/00A61P37/02A61P43/00C07F9/6506C07C2601/10C07C2603/74
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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