PDBsum entry 2p3t

Blood clotting

PDB id: 2p3t

Contents

Protein chains

52 a.a. *

231 a.a. *

Ligands

993

Metals

_CA

_CL

Waters ×172

* Residue conservation analysis

PDB id:

2p3t

Name:

Blood clotting

Title:

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

Structure:

Coagulation factor x. Chain: a. Fragment: egf-like 2 domain. Synonym: stuart factor, stuart-prower factor. Coagulation factor x. Chain: b. Fragment: catalytic domain. Synonym: stuart factor, stuart-prower factor. Ec: 3.4.21.6

Source:

Homo sapiens. Human. Organism_taxid: 9606. Other_details: extracted from blood. Other_details: extracted from blood

Resolution:

1.92Å R-factor: 0.192 R-free: 0.219

Authors:

M.Adler,M.Whitlow

Key ref:

B.Ye et al. (2007). Thiophene-anthranilamides as highly potent and orally available factor Xa inhibitors. J Med Chem, 50, 2967-2980. PubMed id: 17536795

Date:

09-Mar-07 Release date: 22-Jan-08

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 52 a.a.

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 231 a.a.

Enzyme reactions

• Enzyme class: Chains A, B: E.C.3.4.21.6 - coagulation factor Xa.
• Reaction: Preferential cleavage: Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.

J Med Chem 50:2967-2980 (2007)

PubMed id: 17536795

Thiophene-anthranilamides as highly potent and orally available factor Xa inhibitors.

B.Ye, D.O.Arnaiz, Y.L.Chou, B.D.Griedel, R.Karanjawala, W.Lee, M.M.Morrissey, K.L.Sacchi, S.T.Sakata, K.J.Shaw, S.C.Wu, Z.Zhao, M.Adler, S.Cheeseman, W.P.Dole, J.Ewing, R.Fitch, D.Lentz, A.Liang, D.Light, J.Morser, J.Post, G.Rumennik, B.Subramanyam, M.E.Sullivan, R.Vergona, J.Walters, Y.X.Wang, K.A.White, M.Whitlow, M.J.Kochanny.

ABSTRACT

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.