Design, synthesis, and enzymatic evaluation of N-1-acyloxyalkyl- and N-1-oxazolidin-2,4-dion-5-yl-substituted β-lactams as novel inhibitors of human leukocyte elastase


Moreira, Rui, Santana, Ana Bela, Iley, Jim, Neres, João, Douglas, Kenneth T., Horton, Peter N. and Hursthouse, Michael B. (2005) Design, synthesis, and enzymatic evaluation of N-1-acyloxyalkyl- and N-1-oxazolidin-2,4-dion-5-yl-substituted β-lactams as novel inhibitors of human leukocyte elastase. Journal of Medicinal Chemistry, 48, (15), 4861-4870. (doi: 10.1021/jm0501331).

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Original Publication URL: http://dx.doi.org/10.1021/jm0501331

Description/Abstract

Human leukocyte elastase (HLE) is a serine protease that very efficiently degrades various tissue matrix proteins such as elastin. The imbalance between HLE and its endogenous inhibitors leads to excessive elastin proteolysis and is considered to be responsible for the onset of chronic obstructive pulmonary disease (COPD). A novel series of C-3-, C-4-, and N-1-substituted azetidin-2-ones were prepared as potential mechanism-based inhibitors of HLE to restore the protease/antiprotease imbalance. N-Acyloxyalkylazetidin-2-ones, 4, and their carbamate counterparts, 5, are weak HLE inhibitors, being 5 times less active than their bicyclic oxazolidin-2,4-dione-substituted analogues, 6, containing an electron-withdrawing substituent at C-4. Compounds 6 containing a C-4 substituent exist as two diastereomeric pairs of enantiomers, each pair presenting similar inhibitory activity against HLE. Comparative docking experiments with the C-4-substituted oxazolidin-2,4-dione inhibitors 6 suggest that only the 4R,5' S and 4S,5'S diastereomers consistently interact with the beta-lactam carbonyl carbon atom accessible to the serine hydroxyl oxygen.

Item Type: Article
ISSNs: 0022-2623 (print)
Related URLs:
Keywords: neutrophil elastase, chemical-reactivity, 1.84-a resolution, drug design, esters, antibiotics, complex, acid
Subjects: Q Science > QD Chemistry
R Medicine > RS Pharmacy and materia medica
Divisions: University Structure - Pre August 2011 > School of Chemistry
ePrint ID: 20870
Date Deposited: 02 Mar 2006
Last Modified: 27 Mar 2014 18:10
URI: http://eprints.soton.ac.uk/id/eprint/20870

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