Abstract
Human tissular kallikreins (KLKs) are members of (chymo)trypsin-like serine proteases, involved in various physiological pathways. Among the 15 known isoforms in the literature, kallikrein 7 (KLK7) plays a significant role in physiological and pathophysiological processes of the skin, like psoriasis and the Netherton syndrome. Several studies report also its implication in multiple processes leading to invasive and metastatic tumor growth, especially in prostatic, ovarian and pancreatic cancers. Strategies focused on KLK7 inhibition are a promising alternative for the treatment of such dermatological diseases, and to avoid metastatic dissemination. In the last two decades, many synthetic inhibitors of this KLK isoform have been developed. However, most of these molecules exhibit low selectivity and unsuitable physicochemical properties for in vivo use. This thesis is devoted to the synthesis of selective and reversible inhibitors of KLK7. Two series of compounds have been explored. The first one, derived from a screening of pyrido-imidazodiazepinones compounds, which led to the discovery of a reversible and selective inhibitor of KLK7, JMV4967 (IC50 = 57.0 µM). This compound is characterized by the presence of an ortho methyl substituted phenyl group, at position 2 of the diazepine ring. Based on these results, a structure-activity relationships (SAR) study was initiated. The best inhibitions were obtained with JMV4967analogs bearing a 3,4,5- trimethoxyphenyl group or 3,4- dimethoxyphenyl group, at position 2 of the diazepine ring. This study led to the discovery of one compound, JMV5046 (IC50 = 33.5 µM). A biochemical study of JMV5046, highlighted its reversible and competitive behavior against the substrate in the KLK7 active site, as previously observed for the initial hit. The second series was developed from an amino-benzimidazole substituted quinazoline, and a SAR study was also carried out. A chemical reactivity study was also initiated to access two new series of imidazo[1,2-a]pyridine-fused or indole-fused diazepine compounds. This study showed that 2-amino-imidazopyridine could undergo alkylation at position 3 of the ring, in the nitro-Michael reaction context. The obtained Michael adducts could then give, after reduction of the nitro group, the corresponding diazepine derivatives. We also showed that, in the presence of an acyl donor (as an activated amino acid ester), 2-amino-indole was N-acylated, unlike the 2-amino-imidazopyridine which leads to an exclusive C-acylation in the same conditions. The N-acylated derivatives were then used for the indolodiazepines synthesis, using Pictet-Spengler cyclization reaction.The synthesis of these compounds and their inhibiting activity against KLK7 are described. Molecular modeling experiments by in silico docking, to determine the structural requirements for KLK7 inhibition by JMV5046, are also presented.