title: 1,2,4-Triazole derivatives as transient inactivators of kallikreins involved in skin diseases.
abstract: We describe here 1,2,4-triazoles derivatives identified as transient inactivators acting at the nanomolar level on human kallikreins (hK5, hK7 and hK14) and matriptase. Both the nature of the targeted enzymes and structural variations of the inhibitors influence the life-times of acyl-enzymes. These nonpeptidic, transient and low-molecular-weight inhibitors were found to be noncytotoxic against healthy human keratinocytes. These molecules may be useful to counteract dysregulated proteolytic cascades observed in dermatological disorders such as Netherton syndrome.
authors.affiliation: Enzymologie Moléculaire et Fonctionnelle, UR4, Université Pierre et Marie Curie-Sorbonne Universités (UPMC), Case Courrier 256, 7, Quai St Bernard, 75252 Paris Cedex 05, France.
authors.forename: Xiao
authors.initials: X
authors.lastname: Tan
authors.forename: Laetitia
authors.initials: L
authors.lastname: Furio
authors.forename: Michèle
authors.initials: M
authors.lastname: Reboud-Ravaux
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
authors.forename: Alain
authors.initials: A
authors.lastname: Hovnanian
authors.forename: Chahrazade
authors.initials: C
authors.lastname: El Amri
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors*; D015603:Keratinocytes / Q000187:drug effects*; D012871:Skin Diseases / Q000188:drug therapy; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D014230:Triazoles; C045575:1,2,4-triazole; D007610:Kallikreins
keywords: 3-amino-7-methyl-coumarin; AMC; Acyl-enzymes; DMSO; HTS; Inhibitors; Kallikreins; LEKTI; Matriptase; Netherton syndrome; Transient inactivators; dimethyl sulfoxide; hK; high throughput screening; human kallikrein; lympho-epithelial Kazal-type inhibitor