DE19826972A1 - Inhibiting keratinocyte activation and proliferation, for treatment of dermatological disorders such as psoriasis or actinic precancerous states - Google Patents

Inhibiting keratinocyte activation and proliferation, for treatment of dermatological disorders such as psoriasis or actinic precancerous states

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DE19826972A1
DE19826972A1 DE1998126972 DE19826972A DE19826972A1 DE 19826972 A1 DE19826972 A1 DE 19826972A1 DE 1998126972 DE1998126972 DE 1998126972 DE 19826972 A DE19826972 A DE 19826972A DE 19826972 A1 DE19826972 A1 DE 19826972A1
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inhibitors
keratinocytes
enzyme activity
proliferation
amino acid
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Siegfried Ansorge
Ilona Born
Frank Buehling
Juergen Faust
Harald Gollnick
Uwe Lendeckel
Klaus Neubert
Dirk Reinhold
Robert Vetter
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Otto Von Guericke Universitaet Magdeburg
Martin Luther Universitaet Halle Wittenberg
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Otto Von Guericke Universitaet Magdeburg
Martin Luther Universitaet Halle Wittenberg
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    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides

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Abstract

The use of inhibitors (I) of dipeptidyl peptidase IV (DP IV) or analogous enzymes is claimed for inhibiting the activation and proliferation of keratinocytes (including malignantly transformed keratinocytes) and tumor cells derived from keratinocytes.- DETAILED DESCRIPTION - An INDEPENDENT CLAIM is included for (I)-containing pharmaceutical preparations for use as above.- ACTIVITY - Antiinflammatory; dermatological; antipsoriatic; cytostatic.- MECHANISM OF ACTION - Dipeptidyl peptidase IV inhibitor; DNA synthesis inhibitor.- Inhibition of DP IV in keratinocytes suppresses activation and DNA synthesis in these cells and thus suppresses proliferation. Addition of N( epsilon )-4-nitrobenzyloxycarbonyl-L-lysine-thiazolidide (Ia) at 2 mu M reduced DNA synthesis (measured after 72 hours) in cultured NHEK Ad human keratinocytes by ca. 50 %

Description

Die Erfindung beschreibt die Hemmung der Enzymaktivität der Dipeptidylpeptidase IV (DP IV, E. C. 3.4.14.5, CD26) bzw. DP IV analoger Enzyme humaner Keratinozyten durch spezifische Inhibitoren auf der Basis von Aminosäurederivaten, Peptiden oder Peptidderivaten über die die Aktivierung und DNS-Synthese und damit die Proliferation (Zellvermehrung) dieser Zellen supprimiert wird.The invention describes the inhibition of the enzyme activity of dipeptidyl peptidase IV (DP IV, E. C. 3.4.14.5, CD26) or DP IV analogous enzymes of human keratinocytes by specific Inhibitors based on amino acid derivatives, peptides or peptide derivatives via the Activation and DNA synthesis and thus the proliferation (cell proliferation) of these cells is suppressed.

Eine Reihe dermatologischer Erkrankungen gehen mit follikulären und epidermalen Hyperkeratosen und einer verstärkten Keratinozytenproliferation einher. Zu ihnen gehören sowohl entzündliche und nicht entzündliche epidermale Hyperproliferationszustände (z. B. congenitale Ichthyosen und Psoriasis), benigne und maligne umschriebene epidermale clonale Expansionen (z. B. Warzen, Condylome, aktinische Keratosen/Präcancerosen), benigne und maligne follikuläre Hyperproliferationszustände (z. B. Akne) als auch benigne und maligne epitheliale Adnextumoren und primäre und reaktive Nagelzellhyperproliferationen. Detailinformationen dazu sind in Tabelle 2 und Tabelle 3 enthalten.A number of dermatological diseases go with follicular and epidermal Hyperkeratosis and increased keratinocyte proliferation. They include both inflammatory and non-inflammatory epidermal hyperproliferative conditions (eg congenital Ichthyosis and psoriasis), benign and malignant circumscribed epidermal clonal expansions (eg wart, condyloma, actinic keratosis / precancerosis), benign and malignant follicular Hyperproliferative states (eg acne) as well as benign and malignant epithelial adnexal tumors and primary and reactive nail cell hyperproliferations. Detailed information is available in Table 2 and Table 3 included.

Peptidasen wie die Dipeptidylpetidase IV (DP IV, CD26, E. C.3.4.14.5) sind für die Regulation bzw. Modulation von Wechselwirkungen zwischen Zellen besonders interessant, da sie als Ektoenzyme in der Plasmamembran der Zellen lokalisiert sind, Interaktionen mit anderen extrazellulären Strukturen eingehen, pertiderge Botenstoffe durch enzymkatalysierte Hydrolyse aktivieren bzw. inaktivieren und dadurch wichtig für die Zell-Zell-Kommunikation sind [Yaron A, et al.: Proline-dependent structural and biological properties of peptides and proteins. Crit Rev Biochem Mol Biol 1993; 28 : 31-81; Vanhoof G, et al.: Proline motifs in peptides and their biological processing. FASEB J 1995; 9 : 736-744].Peptidases such as dipeptidylpetidase IV (DP IV, CD26, E.C.3.4.14.5) are for regulation or modulation of interactions between cells particularly interesting, since they are considered Ectoenzymes are localized in the plasma membrane of the cells, interacting with others enter extracellular structures, pertiderogenic messengers by enzyme-catalyzed hydrolysis activate or inactivate and are therefore important for cell-cell communication [Yaron A, et al .: Proline-dependent structural and biological properties of peptides and proteins. Crit Rev Biochem Mol Biol 1993; 28: 31-81; Vanhoof G, et al .: Proline motifs in peptides and theirs biological processing. FASEB J 1995; 9: 736-744].

Es ist gezeigt worden, daß die DP IV im Prozeß der Aktivierung und klonalen Expansion von Immunzellen, insbesondere von T-Lymphozyten eine Schlüsselfunktion spielt [Fleischer B: CD26: a surface protease involved in T-cell activation. Immunol Today 1994; 15: 180-184]. Der Enzymaktivität der DP IV kommt dabei eine besondere Rolle zu [Ansorge S. et al.: Membrane­ bound peptidases of lymphocytes: Functional implications. Biomed Biochem Acta 1991; 50: 799-­ 807; Tanaka T, et al. The costimulatory activity of the CD26 antigen requires dipeptidyl peptidase IV enzymatic activity. Proc Natl Acad Sci USA 1993; 90 : 4586-4590]. Verschiedene Funktionen mitogenstimulierter mono-nukleärer Zellen und gereinigter T-Lymphozyten wie DNS-Synthese, Produktion von immunstimulierenden Zytokinen (IL-2, IL-6, IL-10, IL-12, IFN-γ) und Helferfunktionen für B-Zellen (IgG- und IgM-Synthese) können in Gegenwart von spezifischen Inhibitoren der DP IV gehemmt werden [Schön E, et al.: The dipeptidyl peptidase IV, a membrane enzyme involved in the proliferation of T lymphocytes. Biomed. Biochim. Acta 1985; 2, K9-K15; Schön E, et al. The role of dipeptidyl peptidase IV in human T lymphocyte activation. Inhibitors and antibodies against dipeptidyl peptidase IV suppress lymphocyte proliferation and immunoglobulin synthesis in vitro. Eur J Immunol 1987; 17: 1821-1826; Reinhold D, et al. Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor-β1 in PWM-stimulated PBMC and T cells. Immunology 1997; 91: 354-360]. It has been demonstrated that DP IV plays a key role in the process of activation and clonal expansion of immune cells, particularly T lymphocytes [Fleischer B: CD26: a surface protease involved in T-cell activation. Immunol Today 1994; 15: 180-184]. The enzyme activity of DP IV plays a special role here [Ansorge S. et al .: Membrane bound peptidases of lymphocytes: Functional implications. Biomed Biochem Acta 1991; 50: 799-807; Tanaka T, et al. The costimulatory activity of the CD26 antigen requires dipeptidyl peptidase IV enzymatic activity. Proc Natl Acad Sci USA 1993; 90: 4586-4590]. Various functions of mitogen-stimulated mononuclear cells and purified T lymphocytes such as DNA synthesis, production of immunostimulatory cytokines (IL-2, IL-6, IL-10, IL-12, IFN-γ) and helper functions for B cells (IgG and IgM synthesis) can be inhibited in the presence of specific inhibitors of DP IV [Schoen E, et al .: The dipeptidyl peptidase IV, a membrane enzyme involved in the proliferation of T lymphocytes. Biomed. Biochim. Acta 1985; 2, K9-K15; Schön E, et al. The role of dipeptidyl peptidase IV in human T lymphocyte activation. Inhibitors and antibodies against dipeptidyl peptidase IV suppress lymphocyte proliferation and immunoglobulin synthesis in vitro. Eur J Immunol 1987; 17: 1821-1826; Reinhold D, et al. Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor- 1 in PWM-stimulated PBMC and T cells. Immunology 1997; 91: 354-360].

Es ist bereits bekannt, daß die Behandlung von Autoimmunerkrankungen und Transplantatabstoßung durch Hemmung der auf Immunzellen lokalisierten Dipeptidylpetidase IV mit Hilfe von synthetischen Inhibitoren möglich ist (z. B. EP764151 A1, WO09529691, EP731789 A1, EP528858).It is already known that the treatment of autoimmune diseases and Graft rejection by inhibition of immune cell-localized dipeptidylpetidase IV with the aid of synthetic inhibitors is possible (eg EP764151 A1, WO09529691, EP731789 A1, EP528858).

Der Erfindung liegt der überraschende Befund zugrunde, daß eine Hemmung der DP IV- Enzymaktivität von Keratinozyten zu einer Suppression der DNS-Synthese und damit der Proliferation dieser Zellen führt.The invention is based on the surprising finding that an inhibition of the DP IV Enzyme activity of keratinocytes to a suppression of DNA synthesis and thus the Proliferation of these cells leads.

Unsere Erfindung zeigt, daß zur Therapie von sowohl entzündlichen und nicht entzündlichen epidermalen Hyperproliferationszuständen (z. B. congenitale Ichthyosen und Psoriasis), benignen und malignen umschriebenen epidermalen clonalen Expansionen (z. B. Warzen, Condylome, aktinische Keratosen/Präcancerosen), benignen und malignen follikulären Hyperproliferations­ zuständen (z. B. Akne) als auch benignen und malignen epithelialen Adnextumoren und primären und reaktiven Nagelzellhyperproliferationen Effektoren der Dipeptidylpeptidase IV-Enzym­ aktivität geeignet sind.Our invention shows that for the therapy of both inflammatory and non-inflammatory epidermal hyperproliferative states (eg congenital ichthyoses and psoriasis), benign and malignant circumscribed epidermal clonal expansion (eg warts, condylomata, actinic keratoses / precanceroses), benign and malignant follicular hyperproliferations conditions (eg acne) as well as benign and malignant epithelial adnexal tumors and primary and reactive nail cell hyperproliferations effectors of dipeptidyl peptidase IV enzyme activity are suitable.

Die oben genannten Erkrankungen werden bisher topisch mit antiproliferativen und differenzierenden Substanzen (Salizylsäure, Harnstoff, endogene und synthetische Retinoide, Vitamin D3-Derivate, Kortikosteroide) sowie systemisch mit z. T. immunsuppressiven und antiproliferativen Präparaten (z. B. Cyclosporin A, Kortikosteroide, Retinoide) behandelt. Meist kommen nicht Monotherapien sondern Arzneimittelkombinationen zum Einsatz. Insbesondere bei der systemischen Anwendung treten häufig unerwünschte Nebenwirkungen auf. DP IV-Inhibitoren würden bei den genannten Erkrankungen eine neuartige, kostengünstige Therapieform und einen wertvollen alternativen Bestandteil der bestehenden integrierten Therapiekonzepte darstellen.The above diseases are so far topical with antiproliferative and differentiating substances (salicylic acid, urea, endogenous and synthetic retinoids, Vitamin D3 derivatives, corticosteroids) and systemically with z. T. immunosuppressive and antiproliferative preparations (eg cyclosporin A, corticosteroids, retinoids). mostly Monotherapy and drug combinations are not used. Especially at Systemic use often causes undesirable side effects. DP IV inhibitors would be a novel, cost-effective in the diseases mentioned Therapy form and a valuable alternative component of the existing integrated Represent therapy concepts.

Im einzelnen liegen der Erfindung die Befunde zugrunde, daß
In detail, the invention is based on the findings that

  • 1. die DP IV-Enzymaktivität, wie sie auf humanen adulten und neonatalen Keratinozyten exprimiert wird, durch Inhibitoren der DP IV gehemmt werden kann,1. DP IV enzyme activity as found on human adult and neonatal keratinocytes can be inhibited by inhibitors of DP IV can be inhibited
  • 2. diese Inhibitoren die DNS-Synthese von humanen Keratinozyten inhibieren.2. These inhibitors inhibit the DNA synthesis of human keratinocytes.

Die Applikation von Enzyminhibitoren stellt somit bei den genannten Erkrankungen eine neuartige Methode und ergänzende Therapieform zur Behandlung von hyperkeratotischen Prozessen dar.The application of enzyme inhibitors thus represents a novel in the diseases mentioned Method and complementary therapy for the treatment of hyperkeratotic processes.

Die erfindungsgemäß applizierten Effektoren der DP IV können in pharmazeutisch anwendbaren Formulierungskomplexen als Inhibitoren, Substrate, Pseudosubstrate, inhibitorisch wirkende Peptide und Peptidderivate, Antikörper dieses Enzymes zur Anwendung kommen. Bevorzugte Effektoren sind z. B. synthetische DP IV-Inhibitoren wie Aminosäure-thiazolidide, -pyrrolidide, -piperidide. Derartige Verbindungen und deren Herstellung wurden in einem früheren Patent beschrieben (K. Neubert et al., DD 296075 AS).The present invention applied effectors of DP IV can be used in pharmaceutically acceptable Formulation complexes as inhibitors, substrates, pseudo substrates, inhibitory Peptides and peptide derivatives, antibodies of this enzyme are used. preferred Effectors are z. B. synthetic DP IV inhibitors such as amino acid thiazolidides, pyrrolidides, -piperidide. Such compounds and their preparation have been described in an earlier patent (Neubert, K., et al., DD 296075 AS).

Die verwendeten Inhibitoren werden mit bekannten Trägerstoffen verabreicht. Die Verabreichung erfogt einerseits als topische Applikation in Form von z. B. Cremes, Salben, Pasten, Gelen, Lösungen, Sprays, Liposomen, Schüttelmixturen, Hydrokolloidverbänden bzw. anderen dermatologischen Grundlagen/Vehikeln einschließlich instilativer Applikation, andererseits als systemische Applikation zur oralen, transdermalen, intravenösen, subcutanen, intracutanen, intramuskulären Anwendung in geeigneten Rezepturen bzw. in geeigneter Galenik. The inhibitors used are administered with known carriers. The administration erfogt on the one hand as a topical application in the form of z. Creams, ointments, pastes, gels, Solutions, sprays, liposomes, shake mixtures, hydrocolloid dressings or other dermatological bases / vehicles including instilative application, on the other hand as systemic application for oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular use in appropriate formulations or in appropriate galenics.  

Ausführungsbeispieleembodiments Beispiel 1example 1 Inhibierung der Proliferation von humanen Keratinozyten durch Inkubation mit synthetischen DP IV-InhibitorenInhibition of proliferation of human keratinocytes by incubation with synthetic DP IV inhibitors

Unsere Untersuchungen zeigten, daß humane Keratinozyten (sowohl adulte als auch neonatale) die DP IV/CD26 auf ihrer Oberfläche exprimieren (Tabelle 1). Dieser Nachweis erfogte mittels Durchflußzytofluorimetrie und DP IV-Enzymassay in vitro an drei unterschiedlichen adulten Keratinozytenkulturen (NHEK Ad, RUM, ROL) und einer neonatalen Kultur (NHEK Neo).Our studies showed that human keratinocytes (both adult and neonatal) express the DP IV / CD26 on their surface (Table 1). This proof was obtained by means of Flow cytofluorimetry and DP IV enzyme assay in vitro on three different adults Keratinocyte cultures (NHEK Ad, RUM, ROL) and a neonatal culture (NHEK Neo).

Tabelle 1 Table 1

DP IV-Expression und Enzymaktivität humaner Keratinozytenkulturen DP IV expression and enzyme activity of human keratinocyte cultures

Diese Keratinozytenkulturen wurden mit unterschiedlichen Konzentrationen der synthetischen reversiblen DP IV-Inhibitoren Lys[Z(NO2)]-thiazolidid und Lys[Z(NO2)]-pyrrolidid inkubiert und nach 72 Stunden die DNS-Synthese (3H-Thymidineinbau) gemessen.These keratinocyte cultures were incubated with different concentrations of the synthetic reversible DP IV inhibitors Lys [Z (NO 2 )] thiazolidide and Lys [Z (NO 2 )] pyrrolidide and DNA synthesis ( 3 H-thymidine incorporation) was measured after 72 hours ,

Die Diagramme in Abb. 1 zeigen den Einfluß der synthetischen reversiblen DP IV-Inhibitoren Lys[Z(NO2)]-thiazolidid und Lys[Z(NO2)]-pyrrolidid auf die DNS-Synthese humaner Keratinozyten. Wie aus diesen Diagrammen ersichtlich ist, hemmen die DP IV-Inhibitoren dosisabhängig die DNS-Synthese und damit die Zellproliferation aller vier untersuchten Keratinozytenkulturen. Die Vitalität der Zellen war nicht beeinflußt (nicht dokumentiert).The diagrams in Fig. 1 show the influence of the synthetic reversible DP IV inhibitors Lys [Z (NO 2 )] - thiazolidide and Lys [Z (NO 2 )] - pyrrolidide on the DNA synthesis of human keratinocytes. As can be seen from these diagrams, the DP IV inhibitors dose-dependently inhibit the DNA synthesis and thus the cell proliferation of all four investigated keratinocyte cultures. The vitality of the cells was not affected (not documented).

Beispiel 2Example 2 Inhibierung der Proliferation der humanen Keratinozytenzellinie HaCat durch Inkubation mit synthetischen DP IV-InhibitorenInhibition of human keratinocyte cell line HaCat proliferation by incubation with synthetic DP IV inhibitors

Die humane Keratinozytenzellinie HaCat, welche als Zellmodell für die Psoriasis akzeptiert ist, exprimiert ebenfalls die DP IV auf ihrer Oberfläche (21 ±4% CD26-positive Zellen, 30,2 ±5 pkat/106 Zellen). Das Diagramm in Abb. 2 zeigt den Einfluß der synthetischen reversiblen DP IV- Inhibitoren Lys[Z(NO2)]-thiazolidid und Lys[Z(NO2)]-pyrrolidid auf die DNS-Synthese der humanen HaCat-Zellinie. Entsprechend Abb. 2 hemmt eine Inkubation dieser Zellen mit den synthetischen DP IV-Inhibitoren Lys[Z(NO2)]-thiazolidid, Lys[Z(NO2)]-pyrrolidid oder Lys[Z(NO2)]-piperidid die DNS-Synthese und damit die Zellproliferation dosisabhängig. Die Zellvitalität ist durch die Inhibitoren unbeeinflußt (nicht dokumentiert). The human keratinocyte cell line HaCat, which is accepted as a cell model for psoriasis, also expresses the DP IV on its surface (21 ± 4% CD26 positive cells, 30.2 ± 5 pkat / 10 6 cells). The diagram in Fig. 2 shows the influence of the synthetic reversible DP IV inhibitors Lys [Z (NO 2 )] thiazolidide and Lys [Z (NO 2 )] pyrrolidide on the DNA synthesis of the human HaCat cell line. As shown in Fig. 2, incubation of these cells with the synthetic DP IV inhibitors Lys [Z (NO 2 )] thiazolidide, Lys [Z (NO 2 )] pyrrolidide or Lys [Z (NO 2 )] piperidide inhibits DNA Synthesis and thus the cell proliferation dose-dependent. Cell vitality is unaffected by the inhibitors (not documented).

epidermale Hyperproliferationszuständeepidermal hyperproliferative states

z. B. nicht entzündlichz. B. not flammable z. B. entzündlichz. B. flammable - congenitale Ichthyosen- congenital ichthyoses - Psoriasis und Subtypen einschließlich Nägel und Haare- Psoriasis and subtypes including nails and hair - acquirierte Ichthyosen- Acquired ichthyoses - Lichen ruber und Subtypen- lichen planus and subtypes (paraneoplast.)(Paraneoplast.) - Parapsoriasis-Gruppe- Parapsoriasis group - Palmoplantarkeratosen- Palmoplantar keratoses - Keratosis lichenoides- Keratosis lichenoides - congenital- congenital - Lichen simplex chronicus + reaktive lichenoide- Lichen simplex chronicus + reactive lichenoids - erworben/paraneoplast.- acquired / paraneoplast. Hyperproliferationen (z. B. atopische Dermatitis)Hyperproliferations (eg atopic dermatitis) - M. Darier- M. Darier - Lichenoide Reaktionen bei GvHD- Lichenoid reactions in GvHD - Epidermale Naevi- Epidermal nevi - ILVEN-Naevus- ILVEN nevus - Cutis rhomboidalis nuchae- Cutis rhomboidalis nuchae - Lupus erythematodes chron. disc./SCLE/SLE- Lupus erythematosus chron. disc./SCLE/SLE - Acanthosis nigricans- Acanthosis nigricans - Pityriasis rubra pilaris- Pityriasis rubra pilaris - Pachydermie- Pachydermia - M. Grover- M. Grover - Vitiligo- vitiligo - mit Hyperproliferation von Keratinozyten einhergehende ErythrodermienErythroderma associated with hyperproliferation of keratinocytes

umschriebene epidermale clonale Expansioncircumscribed epidermal clonal expansion benignebenign malignemalignant - HPV-assoziiert (Warzen/Condylome- HPV-associated (warts / condylomas - HPV-assoziierte Tumoren- HPV-associated tumors - seborrhoische Keratosen- seborrheic keratoses - aktinische Keratosen/Präcancerosen- actinic keratoses / precanceroses - Hidroakanthome/Porome- Hidroacanthoma / Porome - M. Bowen + Bowen-CAM. Bowen + Bowen-CA - Epidermalcysten- epidermal cysts - M. Paget + Paget-CA- M. Paget + Paget-CA - Milien- Milia - Plattenepithel-CA- squamous epithelium CA. - M. Gottron- M. Gottron - Merkelcell-CAMerkelcell-CA

follikuläre Hyperproliferationszuständefollicular hyperproliferative states benignebenign malignemalignant - Akne- Acne - Haarfollikelzelltumoren- Hair follicular cell tumors - akneiforme follikuläre Reaktionen- acneiform follicular reactions - Proliferierende Trichilemmalcysten- Proliferating trichilemmal cysts - Ulerythema ophryogenes- Uterythema ophryogenes - Mischtumoren- mixed tumors AL=L<- Keratosis follikularisAL = L <- Keratosis follicularis

epitheliale Adnextumorenepithelial adnexal tumors

benignebenign malignemalignant - Porom- Poroma - ekkrine/apokrine CA's und Subtypen- eccrine / apocrine CA's and subtypes - syringoductale Tumoren- Syringoductal tumors - Talgdrüsen-CA- Sebaceous gland CA. AL=L<- HidraadenomeAL = L <- Hidraadenome

primäre und reaktive Nagelzellhyperproliferationprimary and reactive nail cell hyperproliferation nicht infektiösnot infectious - congenital- congenital erworbenacquired z. B. Pachyonychienz. B. pachyonychia infektiös bei Mykoseninfectious in mycoses

Claims (10)

1. Verwendung von Inhibitoren der Dipeptidylpeptidase IV (DP IV)-Enzymaktivität bzw. DP IV-analoger-Enzymaktivität zur Hemmung der Aktivierung und Proliferation von Keratinozyten und von maligne transformierten Keratinozyten, also von von Keratinozyten abstammenden Tumorzellen.1. Use of Inhibitors of Dipeptidyl Peptidase IV (DP IV) Enzyme Activity or DP IV analog enzyme activity to inhibit the activation and proliferation of Keratinocytes and malignant transformed keratinocytes, that is from keratinocytes derived tumor cells. 2. Verwendung gemäß Anspruch 1, dadurch gekennzeichnet, daß die Inhibitoren der Dipeptidylpeptidase IV (DP IV)-Enzymaktivität bzw. DP IV-analoger Enzymaktivität zur Therapie von sowohl entzündlichen und nicht entzündlichen epidermalen Hyperproliferations­ zuständen (z. B. congenitale Ichthyosen und Psoriasis), benignen und malignen umschriebenen epidermalen clonalen Expansionen (z. B. Warzen, Condylome, aktinische Keratosen/­ Präcancerosen), benignen und malignen Hyperproliferationszuständen (z. B. Akne) als auch benignen und malignen epithelialen Adnextumoren und primären und reaktiven Nagelzellhyperproliferationen dienen.2. Use according to claim 1, characterized in that the inhibitors of Dipeptidyl peptidase IV (DP IV) enzyme activity or DP IV-analogous enzyme activity for Therapy of both inflammatory and non-inflammatory epidermal hyperproliferations conditions (eg, congenital ichthyosis and psoriasis), benign and malignant circumscribed epidermal clonal expansion (eg, warts, condylomas, actinic keratoses) Precancerosis), benign and malignant hyperproliferative conditions (eg acne) as well benign and malignant epithelial adnexal tumors and primary and reactive Nail cell hyperproliferations serve. 3. Verwendung gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß als Inhibitoren der Dipeptidylpeptidase IV (DP IV)-Enzymaktivität bzw. DP IV-analoger Enzymaktivität Aminosäurederivate, Peptide oder Peptidderivate bzw. Kombinationen der genannten Effektoren verwendet werden.3. Use according to claim 1 or 2, characterized in that as inhibitors of Dipeptidyl peptidase IV (DP IV) enzyme activity or DP IV-analogous enzyme activity Amino acid derivatives, peptides or peptide derivatives or combinations of said effectors be used. 4. Verwendung gemäß Anspruch 1, 2 und 3, dadurch gekennzeichnet, daß die Verbindungen synthetische DP IV-Inhibitoren, bevorzugt Xaa-Pro-Dipeptide, entsprechende Peptidderivate und deren Salze bzw. Aminosäure (Xaa)-amide, entsprechende Aminosäureamidderivate und deren Salze sind, wobei Xaa eine α-Aminosäure bzw. ein α-Aminosäurederivat bevorzugt L-Tryptophan, L-Isoleucin, L-Valin, Nε-4-Nitrobenzyloxycarbonyi-L-Lysin ist und als Amidstruktur cyclische Amine z. B. Pyrrolidin, Piperidin, Thiazolidin und deren Derivate fungieren.4. Use according to claim 1, 2 and 3, characterized in that the compounds are synthetic DP IV inhibitors, preferably Xaa-Pro-dipeptides, corresponding peptide derivatives and their salts or amino acid (Xaa) amides, corresponding amino acid amide derivatives and their salts wherein Xaa is an α-amino acid or an α-amino acid derivative is preferably L-tryptophan, L-isoleucine, L-valine, N ε -4-Nitrobenzyloxycarbonyi-L-lysine and cyclic amines as amide structure z. As pyrrolidine, piperidine, thiazolidine and derivatives thereof. 5. Verwendung gemäß Anspruch 1, 2, 3 und 4, dadurch gekennzeichnet, daß Aminosäureamide z. B. Nε-4-Nitrobenzyloxycarbonyl-L-Lysin-thiazolidid, -pyrrolidid und -piperidid sowie das entsprechende 2-Cyanothiazolidid-, 2-Cyanopyrrolidid- und 2-Cyanopiperidid-Derivat bevorzugt als DP IV-Inhibitoren eingesetzt werden.5. Use according to claim 1, 2, 3 and 4, characterized in that amino acid amides z. B. N ε -4-nitrobenzyloxycarbonyl-L-lysine thiazolidide, pyrrolidide and piperidide and the corresponding 2-Cyanothiazolidid-, 2-Cyanopyrrolidid- and 2-Cyanopiperidid derivative are preferably used as DP IV inhibitors. 6. Pharmazeutische Zubereitungen zur Behandlung von Zuständen oder Störungen unter Verwendung von Inhibitoren der Dipeptidylpeptidase IV (DP IV)-Enzymaktivität bzw. DP-analoger Enzymaktivität, die eine Hemmung der Aktivierung und Proliferation von Keratinozyten und von maligne transformierten Keratinozyten bewirken.6. Pharmaceutical preparations for the treatment of conditions or disorders using inhibitors of dipeptidyl peptidase IV (DP IV) enzyme activity or DP-analogous enzyme activity, an inhibition of activation and proliferation of keratinocytes and malignant effect transformed keratinocytes. 7. Pharmazeutische Zubereitung gemäß Anspruch 6 zur Behandlung von dermatologischen Autoimmunerkrankungen mit hyperkeratotischen Effioreszenzen (cutaner und systemischer Lupus erythematodes), von Psoriasis, von dermato-onkologischen Erkrankungen (Plattenepithelkarzinom, Basaliom, Aktinische Präkanzerosen, Keratokanthom, u. a.) und von Hyperkeratotischen Erbkrankheiten (Ichtyosen).7. Pharmaceutical preparation according to claim 6 for the treatment of dermatological Autoimmune diseases with hyperkeratotic effiorescences (cutaneous and systemic lupus erythematosus), psoriasis, dermato-oncological diseases (squamous cell carcinoma, Basalioma, actinic precancerous lesions, keratocanthoma, u. a.) and hyperkeratotic Hereditary diseases (ichthyoses). 8. Pharmazeutische Zubereitung nach Anspruch 6 oder 7, dadurch gekennzeichnet, daß die DP IV-Inhibitoren bevorzugt Substanzen gemäß Anspruch 4 und 5 sind. 8. Pharmaceutical preparation according to claim 6 or 7, characterized in that the DP IV inhibitors are preferably substances according to claims 4 and 5.   9. Verwendung von Inhibitoren oder pharmazeutische Zubereitung gemäß Ansprüche 1 bis 8 als topische Applikation in Form von z. B. Cremes, Salben, Pasten, Gelen, Lösungen, Sprays, Liposomen, Schüttelmixturen, Hydrokolloidverbänden bzw. anderen dermatologischen Grundlagen/Vehikeln, einschließlich instilativer Applikation.9. Use of inhibitors or pharmaceutical preparation according to claims 1 to 8 as topical application in the form of z. Creams, ointments, pastes, gels, solutions, sprays, liposomes, Shaking mixtures, hydrocolloid dressings or other dermatological bases / vehicles, including instilative application. 10. Verwendung von Inhibitoren oder pharmazeutische Zubereitung gemäß Anspruch 1 bis 8 als systemische Anwendung zur oralen, transdermalen, intravenösen, subcutanen, intracutanen, intramuskulären Applikation in entsprechenden Rezepturen bzw. in geeigneter Galenik mit üblichen Trägerstoffen, Hilfsmitteln und/oder Zusatzstoffen.10. Use of inhibitors or pharmaceutical preparation according to claim 1 to 8 as systemic use for oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular administration in appropriate formulations or in appropriate galenics with conventional Carriers, auxiliaries and / or additives.
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US6890905B2 (en) 2001-04-02 2005-05-10 Prosidion Limited Methods for improving islet signaling in diabetes mellitus and for its prevention
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US7368421B2 (en) 2001-06-27 2008-05-06 Probiodrug Ag Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis
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WO2003002595A3 (en) * 2001-06-27 2003-05-08 Probiodrug Ag Dipeptidyl peptidase iv inhibitors and their uses as anti-cancer agents
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US6844316B2 (en) 2001-09-06 2005-01-18 Probiodrug Ag Inhibitors of dipeptidyl peptidase I
WO2003024942A1 (en) * 2001-09-14 2003-03-27 Mitsubishi Pharma Corporation Thiazolidine derivative and medicinal use thereof
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US7790725B2 (en) 2001-09-14 2010-09-07 Mitsubishi Tanabe Pharma Corporation Thiazolidine derivatives and medicinal use thereof
US7608577B2 (en) 2001-10-12 2009-10-27 Osi Pharmaceuticals, Inc. Peptidyl ketones as inhibitors of DPIV
US6946480B2 (en) 2002-02-28 2005-09-20 Hans-Ulrich Demuth Glutaminyl based DPIV inhibitors
WO2003077935A1 (en) * 2002-03-15 2003-09-25 Imtm Institut Für Medizintechnologie Magdeburg Gmbh Use of enzyme inhibitors with aminopeptidase n and/or dipeptidylpeptidase iv activities and pharmaceutical preparations produced therefrom for the therapy and prevention of dermatological diseases with seborrhoeic hyperproliferation and altered differentiation states
AU2003214105B2 (en) * 2002-03-15 2008-11-13 Siegfried Ansorge Use of enzyme inhibitors with aminopeptidase N and/or dipeptidylpeptidase IV activities and pharmaceutical preparations produced therefrom for the therapy and prevention of dermatological diseases with seborrhoeic hyperproliferation and altered differentiation states
US7371871B2 (en) 2003-05-05 2008-05-13 Probiodrug Ag Inhibitors of glutaminyl cyclase
US7381537B2 (en) 2003-05-05 2008-06-03 Probiodrug Ag Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease
US8076330B2 (en) 2005-04-22 2011-12-13 Amgen Inc. Dipeptidyl peptidase-IV inhibitors

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