Optimization of O3-acyl kojic acid derivatives as potent and selective human neutrophil elastase inhibitors.
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.
Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa , Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Susana D
SD
Lucas
Lídia M
LM
Gonçalves
Luís A R
LA
Carvalho
Henrique F
HF
Correia
Eduardo M R
EM
Da Costa
Romina A
RA
Guedes
Rui
R
Moreira
Rita C
RC
Guedes
D000818:Animals; D002460:Cell Line; D004355:Drug Stability; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D019272:Leukocyte Elastase / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D053491:Proteinase Inhibitory Proteins, Secretory / Q000138:chemical synthesis* / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis / Q000494:pharmacology; D011753:Pyrones / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship
D053491:Proteinase Inhibitory Proteins, Secretory; D011728:Pyridones; D011753:Pyrones; C011890:kojic acid; D019272:Leukocyte Elastase