Pyrido-imidazodiazepinones as a new class of reversible inhibitors of human kallikrein 7.

Autor: Arama DP; Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Université de Montpellier, UFR des Sciences Pharmaceutiques et Biologiques, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France., Soualmia F; Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular & Functional Enzymology, 7 Quai St Bernard, F-75005 Paris, France., Lisowski V; Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Université de Montpellier, UFR des Sciences Pharmaceutiques et Biologiques, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France., Longevial JF; Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Université de Montpellier, UFR des Sciences Pharmaceutiques et Biologiques, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France., Bosc E; Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular & Functional Enzymology, 7 Quai St Bernard, F-75005 Paris, France., Maillard LT; Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Université de Montpellier, UFR des Sciences Pharmaceutiques et Biologiques, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France., Martinez J; Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Université de Montpellier, UFR des Sciences Pharmaceutiques et Biologiques, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France., Masurier N; Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Université de Montpellier, UFR des Sciences Pharmaceutiques et Biologiques, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France. Electronic address: nicolas.masurier@univ-montp1.fr., El Amri C; Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular & Functional Enzymology, 7 Quai St Bernard, F-75005 Paris, France. Electronic address: chahrazade.el_amri@upmc.fr.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2015 Mar 26; Vol. 93, pp. 202-13. Date of Electronic Publication: 2015 Feb 07.
DOI: 10.1016/j.ejmech.2015.02.008
Abstrakt: The human tissue kallikrein-7 (KLK7) is a chymotryptic serine protease member of tissue kallikrein family. KLK7 is involved in skin homeostasis and inflammation. Excess of KLK7 activity is also associated with tumor metastasis processes, especially in ovarian carcinomas, prostatic and pancreatic cancers. Development of Kallikrein 7 inhibitors is thus of great interest in oncology but also for treating skin diseases. Most of the developed synthetic inhibitors present several drawbacks such as poor selectivity and unsuitable physico-chemical properties for in vivo use. Recently, we described a practical sequence for the synthesis of imidazopyridine-fused [1,3]-diazepines. Here, we report the identification of pyrido-imidazodiazepinone core as a new potential scaffold to develop selective and competitive inhibitors of kallikrein-related peptidase 7. Structure-activity relationships (SAR), inhibition mechanisms and selectivity as well as cytotoxicity against selected cancer cell lines were investigated.
(Copyright © 2015 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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