Discovery of a new isomannide-based peptidomimetic synthetized by Ugi multicomponent reaction as human tissue kallikrein 1 inhibitor.

Abstract

Human kallikrein 1 (KLK1) is the most extensively studied member of this family and plays a major role in inflammation processes. From Ugi multicomponent reactions, isomannide-based peptidomimetic 10 and 13 where synthesized and showed low micromolar values of IC50 for KLK1 The most active compound (10) presented competitive mechanism, with three structural modifications important to interact with active site residues which corroborates its KLK1 inhibition. Finally, the most active compound also showed good ADMET profile, which indicates compound 10 as a potential hit in the search for new KLK1 inhibitors with low side effects.

• Authors: Thalita G Barros, Jorge A N Santos, Bruno E G de Souza, Ana Carolina R Sodero, Alessandra M T de Souza, Dayane P da Silva, Carlos Rangel Rodrigues, Sergio Pinheiro, Luiza R S Dias, Bárbara Abrahim-Vieira, Luciano Puzer, Estela M F Muri
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 27 Issue 2 Pg. 314-318 (01 15 2017) ISSN: 1464-3405 [Electronic] England
• PMID: 27914800 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• 1,4-3,6-dianhydromannitol
• Bridged Bicyclo Compounds, Heterocyclic
• Enzyme Inhibitors
• Peptidomimetics
• KLK10 protein, human
• Kallikreins

Topics

• Bridged Bicyclo Compounds, Heterocyclic (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Discovery
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Kallikreins (antagonists & inhibitors, metabolism)
• Models, Molecular
• Molecular Structure
• Peptidomimetics (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship