Design, Synthesis, and Enzymatic Evaluation of N1-Acyloxyalkyl- and N1-Oxazolidin-2,4-dion-5-yl-Substituted beta-lactams as Novel Inhibitors of Human Leukocyte Elastase

Moreira, Rui; Santana, Ana Bela; Iley, Jim; Neres, Joao; Douglas, Kenneth T.; Horton, Peter N. and Hursthouse, Michael B. (2005). Design, Synthesis, and Enzymatic Evaluation of N1-Acyloxyalkyl- and N1-Oxazolidin-2,4-dion-5-yl-Substituted beta-lactams as Novel Inhibitors of Human Leukocyte Elastase. Journal of Medicinal Chemistry, 48(15) pp. 4861–4870.

DOI: https://doi.org/10.1021/jm0501331

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 â-lactam carbonyl carbon atom
accessible to the serine hydroxyl oxygen.

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