1mu6
From Proteopedia
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|PDB= 1mu6 |SIZE=350|CAPTION= <scene name='initialview01'>1mu6</scene>, resolution 1.99Å | |PDB= 1mu6 |SIZE=350|CAPTION= <scene name='initialview01'>1mu6</scene>, resolution 1.99Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=CDA:2-(6-CHLORO-3-{[2,2-DIFLUORO-2-(2-PYRIDINYL)ETHYL]AMINO}-2-OXO-1(2H)-PYRAZINYL)-N-[(2-FLUORO-6-PYRIDINYL)METHYL]ACETAMIDE'>CDA</scene> | + | |LIGAND= <scene name='pdbligand=CDA:2-(6-CHLORO-3-{[2,2-DIFLUORO-2-(2-PYRIDINYL)ETHYL]AMINO}-2-OXO-1(2H)-PYRAZINYL)-N-[(2-FLUORO-6-PYRIDINYL)METHYL]ACETAMIDE'>CDA</scene>, <scene name='pdbligand=TYS:SULFONATED+TYROSINE'>TYS</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] </span> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1mu8|1MU8]], [[1mue|1MUE]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1mu6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1mu6 OCA], [http://www.ebi.ac.uk/pdbsum/1mu6 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1mu6 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives. | Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Dysprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hyperprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hypoprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Wong, B.]] | [[Category: Wong, B.]] | ||
[[Category: Yan, Y.]] | [[Category: Yan, Y.]] | ||
| - | [[Category: CDA]] | ||
[[Category: blood clotting]] | [[Category: blood clotting]] | ||
[[Category: hydrolase]] | [[Category: hydrolase]] | ||
| - | ''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 22:21:11 2008'' |
Revision as of 19:21, 30 March 2008
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| , resolution 1.99Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||
| Related: | 1MU8, 1MUE
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of Thrombin in Complex with L-378,622
Overview
Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.
About this Structure
1MU6 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines., Burgey CS, Robinson KA, Lyle TA, Sanderson PE, Lewis SD, Lucas BJ, Krueger JA, Singh R, Miller-Stein C, White RB, Wong B, Lyle EA, Williams PD, Coburn CA, Dorsey BD, Barrow JC, Stranieri MT, Holahan MA, Sitko GR, Cook JJ, McMasters DR, McDonough CM, Sanders WM, Wallace AA, Clayton FC, Bohn D, Leonard YM, Detwiler TJ Jr, Lynch JJ Jr, Yan Y, Chen Z, Kuo L, Gardell SJ, Shafer JA, Vacca JP, J Med Chem. 2003 Feb 13;46(4):461-73. PMID:12570369
Page seeded by OCA on Sun Mar 30 22:21:11 2008
Categories: Homo sapiens | Protein complex | Thrombin | Barrow, J C. | Bohn, D. | Burgey, C S. | Chen, Z. | Clayton, F C. | Coburn, C A. | Cook, J J. | Dorsey, B D. | Gardell, S J. | Holahan, M A. | Jr., J J.Lynch. | Jr., T J.Detwiler. | Krueger, J A. | Kuo, L. | Leonard, Y M. | Lewis, S D. | Lucas, B J. | Lyle, E A. | Lyle, T A. | McDonough, C M. | McMasters, D R. | Miller-Stein, C. | Robinson, K A. | Sanders, W M. | Sanderson, P E. | Shafer, J A. | Singh, R. | Sitko, G R. | Stranieri, M T. | Vacca, J P.J. | Wallace, A A. | White, R B. | Williams, P D. | Wong, B. | Yan, Y. | Blood clotting | Hydrolase
