Optimization of O3-acyl kojic acid derivatives as potent and selective human neutrophil elastase inhibitors

Susana D Lucas; Lídia M Gonçalves; Luís A R Carvalho; Henrique F Correia; Eduardo M R Da Costa; Romina A Guedes; Rui Moreira; Rita C Guedes

doi:10.1021/jm4011725

Optimization of O3-acyl kojic acid derivatives as potent and selective human neutrophil elastase inhibitors

J Med Chem. 2013 Dec 12;56(23):9802-6. doi: 10.1021/jm4011725. Epub 2013 Nov 20.

Authors

Susana D Lucas¹, Lídia M Gonçalves, Luís A R Carvalho, Henrique F Correia, Eduardo M R Da Costa, Romina A Guedes, Rui Moreira, Rita C Guedes

Affiliation

¹ Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa , Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.

PMID: 24224573
DOI: 10.1021/jm4011725

Abstract

Human neutrophil elastase (HNE) is an attractive target for treating chronic and acute inflammatory lung diseases. An optimization campaign of the kojic acid scaffold to develop new potent HNE inhibitors is reported. O3-Pivaloyl derivatives were shown to be the most potent inhibitors with IC5o values down to 80 nM. These compounds presented excellent selectivity and cytotoxicity profiles with suitable ligand efficiency.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Drug Stability
Humans
Inhibitory Concentration 50
Kinetics
Leukocyte Elastase / metabolism*
Microsomes, Liver / metabolism
Molecular Docking Simulation
Proteinase Inhibitory Proteins, Secretory / chemical synthesis*
Proteinase Inhibitory Proteins, Secretory / pharmacology
Pyridones / chemical synthesis
Pyridones / pharmacology
Pyrones / chemistry*
Rats
Structure-Activity Relationship

Substances

Proteinase Inhibitory Proteins, Secretory
Pyridones
Pyrones
kojic acid
Leukocyte Elastase