1h1b

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spinqualitylabelsall models 1h1b, resolution 2.0Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF HUMAN NEUTROPHIL ELASTASE COMPLEXED WITH AN INHIBITOR (GW475151)

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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.

Disease

Known diseases associated with this structure: Hematopoiesis, cyclic OMIM:[130130], Neutropenia, congenital OMIM:[130130]

About this Structure

1H1B is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Leukocyte elastase, with EC number 3.4.21.37 Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

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)., Macdonald SJ, Dowle MD, Harrison LA, Clarke GD, Inglis GG, Johnson MR, Shah P, Smith RA, Amour A, Fleetwood G, Humphreys DC, Molloy CR, Dixon M, Godward RE, Wonacott AJ, Singh OM, Hodgson ST, Hardy GW, J Med Chem. 2002 Aug 29;45(18):3878-90. PMID:12190311

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