Discovery of Further Pyrrolidine trans-Lactams as Inhibitors of Human Neutrophil Elastase (HNE) with Potential as Development Candidates and the Crystal Structure of HNE Complexed with an Inhibitor (GW475151)

Described herein is a modern approach to the rapid preparation and evaluation of compounds as potential back-up drug candidates. GW311616A, 1, a derivative of pyrrolidine trans-lactams, has previously been described as a potent, orally active inhibitor of human neutrophil elastase (HNE) for the trea...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2002-08, Vol.45 (18), p.3878-3890
Main Authors: Macdonald, Simon J. F, Dowle, Michael D, Harrison, Lee A, Clarke, Geoffrey D. E, Inglis, Graham G. A, Johnson, Martin R, Shah, Pritom, Smith, Robin A, Amour, Augustin, Fleetwood, Gill, Humphreys, Davina C, Molloy, Christopher R, Dixon, Mary, Godward, Rosalind E, Wonacott, Alan J, Singh, Onkar M. P, Hodgson, Simon T, Hardy, George W
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Combinatorial Chemistry Techniques
Crystallography, X-Ray
Dogs
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Humans
Lactams - chemical synthesis
Lactams - pharmacokinetics
Lactams - pharmacology
Leukocyte Elastase - antagonists & inhibitors
Leukocyte Elastase - blood
Leukocyte Elastase - chemistry
Male
Medical sciences
Models, Molecular
Molecular Structure
Pharmacology. Drug treatments
Pyrroles - chemical synthesis
Pyrroles - pharmacokinetics
Pyrroles - pharmacology
Pyrrolidines - chemical synthesis
Pyrrolidines - pharmacokinetics
Pyrrolidines - pharmacology
Rats
Respiratory system
Stereoisomerism
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - pharmacokinetics
Sulfonamides - pharmacology
Swine
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Summary:Described herein is a modern approach to the rapid preparation and evaluation of compounds as potential back-up drug candidates. GW311616A, 1, a derivative of pyrrolidine trans-lactams, has previously been described as a potent, orally active inhibitor of human neutrophil elastase (HNE) for the treatment of respiratory disease. These properties made it a suitable candidate for development. Described here is the discovery of three further derivatives of pyrrolidine trans-lactams, which fulfill the criteria required for back-up candidates 28, 29, and 32. These include increased activity in inhibiting HNE in human whole blood (HWB) and comparable pharmacokinetic properties, in particular clearance, in two species. To provide a rapid assessment of clearance, cassette dosing in dog was used. Modern array techniques, including the synthesis of mixtures, were used to synthesize compounds rapidly. Having selected three potential compounds as back-up candidates, they were prepared as single enantiomers and profiled in in vitro and in vivo assays and evaluated pharmacokinetically in rat and dog. These compounds are highly potent and selective HNE inhibitors, with a prolonged pharmacodynamic action. Pharmacokinetically, these compounds are comparable with 1 while they are more potent in HWB. Compound 28, however, has a higher clearance. One of these compounds, 32, was cocrystallized with HNE, and features of this structure are described and compared with the cocrystal structure of 1 in porcine pancreatic elastase.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm020881f