Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 53, Issue 1, Pages 241-253Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm901082k
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Funding
- Fundacao para a Ciencia e Tecnologia (FCT, Portugal) [PTDC/QUI/64056/2006, SFRH/BD/17534/2004]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/17534/2004, PTDC/QUI/64056/2006] Funding Source: FCT
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Human leukocyte elastase (HLE) is a serine protease stored in and secreted from neutrophils that plays a determinant role in the pathogenesis of several lung diseases. 4-Oxo-beta-lactams, previously reported as acylating agents of porcine pancreatic elastase, were found to be selective and potent inhibitors of HLE. Structure-activity relationship analysis showed that inhibitory activity is very sensitive to the nature of C-3 substituents, with small alkyl substituents such as a gem-diethyl group improving the inhibitory potency when compared to gem-methyl benzyl or ethyl benzyl counterparts. 4-Oxo-beta-lactams containing a heteroarylthiomethyl group on the para position of an N-1-aryl moiety afforded highly potent and selective inhibition of FILE, even at a very low inhibitor to enzyme ratio, as shown by the k(on) value of 3.24 x 10(6) M-1 s(-1) for 6f. The corresponding ortho isomers were 40- to 90-fold less potent.
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