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Intracellular inhibition of human neutrophil elastase by orally active pyrrolidine-trans-lactams.

Macdonald, S J; Dowle, M D; Harrison, L A; Spooner, J E; Shah, P; Johnson, M R; Inglis, G G; Clarke, G D; Belton, D J; Smith, R A; Molloy, C R; Dixon, M; Murkitt, G; Godward, R E; Skarzynski, T; Singh, O M; Kumar, K A; Hodgson, S T; McDonald, E; Hardy, G W; Finch, H; Humphreys, D C; Fleetwood, G.

Bioorg Med Chem Lett ; 11(2): 243-6, 2001 Jan 22.

Article in English | MEDLINE | ID: mdl-11206469

ABSTRACT

Described are the acylation binding of trans-lactam 1 to porcine pancreatic elastase, the selection of the SO2Me activating group for the lactam N which also confers metabolic stability in hamster liver microsomes, the introduction of aqueous solubility through the piperidine salt 9, the in vivo oral activity of 9 and its bioavailability, and the introduction of 9 as an intracellular neutrophil elastase inhibitor.

Subject(s)

Lactams/pharmacokinetics , Leukocyte Elastase/antagonists & inhibitors , Neutrophils/drug effects , Acylation , Administration, Oral , Animals , Binding Sites , Cricetinae , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Lactams/chemistry , Lactams/pharmacology , Models, Molecular , Neutrophils/enzymology , Pancreas/enzymology , Protein Binding , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Solubility , Structure-Activity Relationship , Swine

ABSTRACT

Subject(s)

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