3-Acyltetramic acids as a novel class of inhibitors for human kallikreins 5 and 7. Issue 9 (1st May 2019)

• Record Type: Journal Article
• Authors: de Souza, Acácio S.; Pacheco, Barbara D.C.; Pinheiro, Sergio; Muri, Estela M.F.; Dias, Luiza R.S.; Lima, Camilo H.S.; Garrett, Rafael; de Moraes, Mariana B.M.; de Souza, Bruno E.G.; Puzer, Luciano
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 9(2019)
• Page Start: 1094
• Page End: 1098
• Publication Date: 2019-05-01
• Subjects: Acyltetramic acids -- Kallikrein -- Trypsin -- Inhibitors -- Molecular modelling; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.02.031
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Human kallikreins 5 and 7 (KLK5 and KLK7) exhibit trypsin- and chymotrypsin-like activities and are involved in pathologies related to skin desquamation process. A series of new 3-acyltetramic acids were developed as a novel class of inhibitors of KLK5, KLK7 and trypsin enzymes. The nature and length of the acyl chain is crucial to the KLK5, KLK7 and trypsin inhibition activities, and the most potent compounds (but not the most selective)2b, 2c and2g showed low micromolar IC50 values. While very few of the compounds were selective for KLK5, the selective inhibition of trypsin against chymotrypsin was achieved. Our molecular modelling studies revealed that the double bond in2g provided the best fit in the binding site of KLK5, while the hydrogen bonding interactions modulated the best fit of2c in the binding site of KLK7 due to the hydrophobicity of the cavity.