4-Oxo-β-lactams (Azetidine-2,4-diones) Are Potent and Selective Inhibitors of Human Leukocyte Elastase

Mulchande, Jalmira; Oliveira, Rudi; Carrasco, Marta; Gouveia, Luís; Guedes, Rita C.; Iley, Jim and Moreira, Rui (2010). 4-Oxo-β-lactams (Azetidine-2,4-diones) Are Potent and Selective Inhibitors of Human Leukocyte Elastase. Journal of Medicinal Chemistry, 53(1) pp. 241–253.

DOI: https://doi.org/10.1021/jm901082k


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-β-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-β-lactams containing a heteroarylthiomethyl group on the para position of an N1-aryl moiety afforded highly potent and selective inhibition of HLE, even at a very low inhibitor to enzyme ratio, as shown by the kon value of 3.24 × 106 M−1 s−1 for 6f. The corresponding ortho isomers were 40- to 90-fold less potent.

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