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

Dominique P Arama (1) , Feryel Soualmia (2) , Vincent Lisowski (1) , Jean-François Longevial (1) , Elodie Bosc (2) , Ludovic T Maillard (1) , Jean Martinez (1) , Nicolas Masurier (1) , Chahrazade El Amri (2)

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
2 B2A - Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing

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.

Keywords: Imidazo[1; 2-a]pyridine; Polyfused heterocycles; Diazepinones; Serine protease; Human tissue kallikrein 7; Non-covalent inhibitors

Domains: Chemical Sciences; Pharmaceutical sciences; Human health and pathology

Dominique P Arama, Feryel Soualmia, Vincent Lisowski, Jean-François Longevial, Elodie Bosc, et al.. Pyrido-imidazodiazepinones as a new class of reversible inhibitors of human kallikrein 7. European Journal of Medicinal Chemistry, 2015, 93, pp.202-213. ⟨10.1016/j.ejmech.2015.02.008⟩. ⟨hal-01120269⟩