1H1B

Crystal structure of human neutrophil elastase complexed with an inhibitor (GW475151)

Summary for 1H1B

• Entry DOI: 10.2210/pdb1h1b/pdb
• Related: 1B0F 1HNE 1PPF 1PPG
• Descriptor: LEUKOCYTE ELASTASE, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, (2S)-3-METHYL-2-((2R,3S)-3-[(METHYLSULFONYL)AMINO]-1-{[2-(PYRROLIDIN-1-YLMETHYL)-1,3-OXAZOL-4-YL]CARBONYL}PYRROLIDIN-2-YL)BUTANOIC ACID, ... (4 entities in total)
• Functional Keywords: hydrolase, serine protease
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 48992.42

Authors

Macdonald, S.J.F.,Dowle, M.D.,Harrison, L.A.,Clarke, G.D.E.,Inglis, G.G.A.,Johnson, M.R.,Smith, R.A.,Amour, A.,Fleetwood, G.,Humphreys, D.C.,Molloy, C.R.,Dixon, M.,Godward, R.E.,Wonacott, A.J.,Singh, O.M.P.,Hodgson, S.T.,Hardy, G.W. (deposition date: 2002-07-05, release date: 2002-08-29, Last modification date: 2023-12-13)

Primary citation

Macdonald, S.J.F.,Dowle, M.D.,Harrison, L.A.,Clarke, G.D.E.,Inglis, G.G.A.,Johnson, M.R.,Shah, P.,Smith, R.A.,Amour, A.,Fleetwood, G.,Humphreys, D.C.,Molloy, C.R.,Dixon, M.,Godward, R.E.,Wonacott, A.J.,Singh, O.M.P.,Hodgson, S.T.,Hardy, G.W.
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)
J.Med.Chem., 45:3878-, 2002

PubMed Abstract: 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.

PubMed: 12190311
DOI: 10.1021/JM020881F

Experimental method

X-RAY DIFFRACTION (2 Å)