title: Pyrido-imidazodiazepinones as a new class of reversible inhibitors of human kallikrein 7.
abstract: 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.
authors: 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.
authors: Dominique P
authors: DP
authors: Arama
authors: 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.
authors: Feryel
authors: F
authors: Soualmia
authors: 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.
authors: Vincent
authors: V
authors: Lisowski
authors: 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.
authors: Jean-François
authors: JF
authors: Longevial
authors: 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.
authors: Elodie
authors: E
authors: Bosc
authors: 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.
authors: Ludovic T
authors: LT
authors: Maillard
authors: 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.
authors: Jean
authors: J
authors: Martinez
authors: 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.
authors: Nicolas
authors: N
authors: Masurier
authors: 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.
authors: Chahrazade
authors: C
authors: El Amri
mesh_terms: D001381:Azepines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D015842:Serine Proteinase Inhibitors; D007610:Kallikreins
keywords: Diazepinones; Human tissue kallikrein 7; Imidazo[1,2-a]pyridine; Non-covalent inhibitors; Polyfused heterocycles; Serine protease