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

• Published in: Bioorganic & medicinal chemistry letters 2017-01, Vol.27 (2), p.314-318
• Main Authors: Barros, Thalita G., Santos, Jorge A.N., de Souza, Bruno E.G., Sodero, Ana Carolina R., de Souza, Alessandra M.T., da Silva, Dayane P., Rodrigues, Carlos Rangel, Pinheiro, Sergio, Dias, Luiza R.S., Abrahim-Vieira, Bárbara, Puzer, Luciano, Muri, Estela M.F.
• Format: Article
• Language: English
• Subjects: Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Inhibitors; Kallikreins; Kallikreins - antagonists & inhibitors; Kallikreins - metabolism; Models, Molecular; Molecular modeling; Molecular Structure; Peptidomimetics; Peptidomimetics - chemical synthesis; Peptidomimetics - chemistry; Peptidomimetics - pharmacology; Structure-Activity Relationship; Ugi reactions
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.11.051

[Display omitted] 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.