1h1b
From Proteopedia
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|PDB= 1h1b |SIZE=350|CAPTION= <scene name='initialview01'>1h1b</scene>, resolution 2.0Å | |PDB= 1h1b |SIZE=350|CAPTION= <scene name='initialview01'>1h1b</scene>, resolution 2.0Å | ||
|SITE= <scene name='pdbsite=AC1:Fuc+Binding+Site+For+Chain+B'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:Fuc+Binding+Site+For+Chain+B'>AC1</scene> | ||
| - | |LIGAND= <scene name='pdbligand=151:(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'>151</scene> | + | |LIGAND= <scene name='pdbligand=151:(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'>151</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Leukocyte_elastase Leukocyte elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.37 3.4.21.37] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Leukocyte_elastase Leukocyte elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.37 3.4.21.37] </span> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1h1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h1b OCA], [http://www.ebi.ac.uk/pdbsum/1h1b PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1h1b RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==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. | 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:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=130130 130130]], Neutropenia, congenital OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=130130 130130]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Smith, R A.]] | [[Category: Smith, R A.]] | ||
[[Category: Wonacott, A J.]] | [[Category: Wonacott, A J.]] | ||
| - | [[Category: 151]] | ||
[[Category: hydrolase]] | [[Category: hydrolase]] | ||
[[Category: neutrophil elastase]] | [[Category: neutrophil elastase]] | ||
[[Category: serine protease]] | [[Category: serine protease]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 20:55:40 2008'' |
Revision as of 17:55, 30 March 2008
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| , resolution 2.0Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | |||||||
| Ligands: | , , | ||||||
| Activity: | Leukocyte elastase, with EC number 3.4.21.37 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF HUMAN NEUTROPHIL ELASTASE COMPLEXED WITH AN INHIBITOR (GW475151)
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.
About this Structure
1H1B is a Single protein structure of sequence from Homo sapiens. 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
Page seeded by OCA on Sun Mar 30 20:55:40 2008
Categories: Homo sapiens | Leukocyte elastase | Single protein | Amour, A. | Clarke, G D.E. | Dixon, M. | Dowle, M D. | Fleetwood, G. | Godward, R E. | Hardy, G W. | Harrison, L A. | Hodgson, S T. | Humphreys, D C. | Inglis, G G.A. | Johnson, M R. | Macdonald, S J.F. | Molloy, C R. | Singh, O M.P. | Smith, R A. | Wonacott, A J. | Hydrolase | Neutrophil elastase | Serine protease
