2p3t: Difference between revisions

Revision as of 19:25, 21 February 2008

Crystal structure of human factor XA complexed with 3-Chloro-4-(2-methylamino-imidazol-1-ylmethyl)-thiophene-2-carboxylic acid [4-chloro-2-(5-chloro-pyridin-2-ylcarbamoyl)-6-methoxy-phenyl]-amide

OverviewOverview

There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.

About this StructureAbout this Structure

2P3T is a Protein complex structure of sequences from Homo sapiens with , and as ligands. Active as Coagulation factor Xa, with EC number 3.4.21.6 Known structural/functional Sites: , and . Full crystallographic information is available from OCA.

ReferenceReference

Thiophene-anthranilamides as highly potent and orally available factor xa inhibitors(1)., Ye B, Arnaiz DO, Chou YL, Griedel BD, Karanjawala R, Lee W, Morrissey MM, Sacchi KL, Sakata ST, Shaw KJ, Wu SC, Zhao Z, Adler M, Cheeseman S, Dole WP, Ewing J, Fitch R, Lentz D, Liang A, Light D, Morser J, Post J, Rumennik G, Subramanyam B, Sullivan ME, Vergona R, Walters J, Wang YX, White KA, Whitlow M, Kochanny MJ, J Med Chem. 2007 Jun 28;50(13):2967-80. Epub 2007 May 31. PMID:17536795

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 ==Overview==
-There remains a high unmet medical need for a safe oral therapy for, thrombotic disorders. The serine protease factor Xa (fXa), with its, central role in the coagulation cascade, is among the more promising, targets for anticoagulant therapy and has been the subject of intensive, drug discovery efforts. Investigation of a hit from high-throughput, screening identified a series of thiophene-substituted anthranilamides as, potent nonamidine fXa inhibitors. Lead optimization by incorporation of, hydrophilic groups led to the discovery of compounds with picomolar, inhibitory potency and micromolar in vitro anticoagulant activity. Based, on their high potency, selectivity, oral pharmacokinetics, and efficacy in, a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK, 810388 (13a), and ZK 813039 (17m) were advanced into development.
+There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.
 ==About this Structure==
-P3T is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CA:'>CA</scene>, <scene name='pdbligand=CL:'>CL</scene> and <scene name='pdbligand=993:'>993</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Coagulation_factor_Xa Coagulation factor Xa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.6 3.4.21.6] Known structural/functional Sites: <scene name='pdbsite=AC1:Ca Binding Site For Residue B 501'>AC1</scene>, <scene name='pdbsite=AC2:Cl Binding Site For Residue B 502'>AC2</scene> and <scene name='pdbsite=AC3:993 Binding Site For Residue B 500'>AC3</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2P3T OCA].
+P3T is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CA:'>CA</scene>, <scene name='pdbligand=CL:'>CL</scene> and <scene name='pdbligand=993:'>993</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Coagulation_factor_Xa Coagulation factor Xa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.6 3.4.21.6] Known structural/functional Sites: <scene name='pdbsite=AC1:Ca+Binding+Site+For+Residue+B+501'>AC1</scene>, <scene name='pdbsite=AC2:Cl+Binding+Site+For+Residue+B+502'>AC2</scene> and <scene name='pdbsite=AC3:993+Binding+Site+For+Residue+B+500'>AC3</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2P3T OCA].
 ==Reference==
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 [[Category: protein inhibitor complex]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 10:50:08 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:25:43 2008''