Discovery and structure-activity relationship of imidazolinylindole derivatives as kallikrein 7 inhibitors

[Display omitted] •Novel imidazolinylindole derivatives as KLK7 inhibitor are disclosed, and their SAR is discussed.•The position of substituent on the benzenesulfonyl moiety strikingly affected the inhibitory activity against mouse KLK7.•X-ray crystal structure analysis of compound 24 bound to mouse KLK7 revealed the structural basis of KLK7 inhibition. A series of imidazolinylindole derivatives were discovered as novel kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Structure-activity relationship (SAR) studies led to the identification of potent human KLK7 inhibitors. By further modification of the benzenesulfonyl moiety to overcome species differences in inhibitory activity, potent inhibitors against both human and mouse KLK7 were identified. Furthermore, the complex structure of 25 with mouse KLK7 could explain the SAR and the cause of the species differences in inhibitory activity.