PDBsum entry 3kl6

Hydrolase

PDB id: 3kl6

Contents

Protein chains

232 a.a. *

50 a.a. *

Ligands

443

EDO ×4

Metals

_CA ×3

Waters ×204

* Residue conservation analysis

PDB id:

3kl6

Name:

Hydrolase

Title:

Discovery of tetrahydropyrimidin-2(1h)-one derivative tak-442: a potent, selective and orally active factor xa inhibitor

Structure:

Coagulation factor x heavy chain. Chain: a. Fragment: factor x heavy chain residues 235-475. Synonym: stuart-prower factor heavy chain. Engineered: yes. Coagulation factor x light chain. Chain: b. Fragment: factor x light chain residues 126-179. Synonym: stuart-prower factor light chain.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: f10. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_taxid: 7108

Resolution:

1.45Å R-factor: 0.195 R-free: 0.212

Authors:

K.Aertgeerts

Key ref:

T.Fujimoto et al. (2010). Discovery of a tetrahydropyrimidin-2(1H)-one derivative (TAK-442) as a potent, selective, and orally active factor Xa inhibitor. J Med Chem, 53, 3517-3531. PubMed id: 20355714

Date:

06-Nov-09 Release date: 01-Dec-09

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 232 a.a.

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 50 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 53:3517-3531 (2010)

PubMed id: 20355714

Discovery of a tetrahydropyrimidin-2(1H)-one derivative (TAK-442) as a potent, selective, and orally active factor Xa inhibitor.

T.Fujimoto, Y.Imaeda, N.Konishi, K.Hiroe, M.Kawamura, G.P.Textor, K.Aertgeerts, K.Kubo.

ABSTRACT

Coagulation enzyme factor Xa (FXa) is a particularly promising target for the development of new anticoagulant agents. We previously reported the imidazo[1,5-c]imidazol-3-one derivative 1 as a potent and orally active FXa inhibitor. However, it was found that 1 predominantly undergoes hydrolysis upon incubation with human liver microsomes, and the human specific metabolic pathway made it difficult to predict the human pharmacokinetics. To address this issue, our synthetic efforts were focused on modification of the imidazo[1,5-c]imidazol-3-one moiety of the active metabolite 3a, derived from 1, which resulted in the discovery of the tetrahydropyrimidin-2(1H)-one derivative 5k as a highly potent and selective FXa inhibitor. Compound 5k showed no detectable amide bond cleavage in human liver microsomes, exhibited a good pharmacokinetic profile in monkeys, and had a potent antithrombotic efficacy in a rabbit model without prolongation of bleeding time. Compound 5k is currently under clinical development with the code name TAK-442.