2feq
From Proteopedia
| Line 4: | Line 4: | ||
|PDB= 2feq |SIZE=350|CAPTION= <scene name='initialview01'>2feq</scene>, resolution 2.44Å | |PDB= 2feq |SIZE=350|CAPTION= <scene name='initialview01'>2feq</scene>, resolution 2.44Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=34P:N-(CARBOXYMETHYL)-3-CYCLOHEXYL-D-ALANYL-N-({4-[(E)-AMINO(IMINO)METHYL]-1,3-THIAZOL-2-YL}METHYL)-L-PROLINAMIDE'>34P</scene> | + | |LIGAND= <scene name='pdbligand=34P:N-(CARBOXYMETHYL)-3-CYCLOHEXYL-D-ALANYL-N-({4-[(E)-AMINO(IMINO)METHYL]-1,3-THIAZOL-2-YL}METHYL)-L-PROLINAMIDE'>34P</scene>, <scene name='pdbligand=ALC:2-AMINO-3-CYCLOHEXYL-PROPIONIC+ACID'>ALC</scene>, <scene name='pdbligand=HYP:4-HYDROXYPROLINE'>HYP</scene>, <scene name='pdbligand=SIN:SUCCINIC+ACID'>SIN</scene>, <scene name='pdbligand=SMF:4-SULFOMETHYL-L-PHENYLALANINE'>SMF</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=[[1o0d|1O0D]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2feq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2feq OCA], [http://www.ebi.ac.uk/pdbsum/2feq PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2feq RCSB]</span> | ||
}} | }} | ||
| Line 14: | Line 17: | ||
==Overview== | ==Overview== | ||
The synthesis and SAR of novel nanomolar thrombin inhibitors with the common backbone HOOC-CH(2)-d-cyclohexylalanyl-3,4-dehydroprolyl-NH-CH(2)-aryl-C(=NH)NH(2) are described together with their ecarin clotting time (ECT) prolongation as measure for thrombin inhibition ex vivo. The aryl P1-moiety mimicking the arginine part of the d-Phe-Pro-Arg derived thrombin inhibitors turned out to be a key component for in vitro potency and in vivo activity. Optimization of this part led to compounds with improved antithrombin activity in rats and dogs after oral administration compared to the recently launched anticoagulant melagatran. | The synthesis and SAR of novel nanomolar thrombin inhibitors with the common backbone HOOC-CH(2)-d-cyclohexylalanyl-3,4-dehydroprolyl-NH-CH(2)-aryl-C(=NH)NH(2) are described together with their ecarin clotting time (ECT) prolongation as measure for thrombin inhibition ex vivo. The aryl P1-moiety mimicking the arginine part of the d-Phe-Pro-Arg derived thrombin inhibitors turned out to be a key component for in vitro potency and in vivo activity. Optimization of this part led to compounds with improved antithrombin activity in rats and dogs after oral administration compared to the recently launched anticoagulant melagatran. | ||
| - | |||
| - | ==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== | ||
| Line 31: | Line 31: | ||
[[Category: Lange, U E.W.]] | [[Category: Lange, U E.W.]] | ||
[[Category: Mack, H.]] | [[Category: Mack, H.]] | ||
| - | [[Category: 34P]] | ||
[[Category: thrombin inhibitor]] | [[Category: thrombin inhibitor]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:01:51 2008'' |
Revision as of 00:01, 31 March 2008
| |||||||
| , resolution 2.44Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , , , | ||||||
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||
| Related: | 1O0D
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
orally active thrombin inhibitors
Overview
The synthesis and SAR of novel nanomolar thrombin inhibitors with the common backbone HOOC-CH(2)-d-cyclohexylalanyl-3,4-dehydroprolyl-NH-CH(2)-aryl-C(=NH)NH(2) are described together with their ecarin clotting time (ECT) prolongation as measure for thrombin inhibition ex vivo. The aryl P1-moiety mimicking the arginine part of the d-Phe-Pro-Arg derived thrombin inhibitors turned out to be a key component for in vitro potency and in vivo activity. Optimization of this part led to compounds with improved antithrombin activity in rats and dogs after oral administration compared to the recently launched anticoagulant melagatran.
About this Structure
2FEQ is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Orally active thrombin inhibitors. Part 1: optimization of the P1-moiety., Mack H, Baucke D, Hornberger W, Lange UE, Seitz W, Hoffken HW, Bioorg Med Chem Lett. 2006 May 15;16(10):2641-7. Epub 2006 Mar 6. PMID:16517159
Page seeded by OCA on Mon Mar 31 03:01:51 2008
