PDBsum entry 2w3k

Hydrolase

PDB id: 2w3k

Contents

Protein chains

234 a.a. *

50 a.a. *

Ligands

L1D

Metals

_CA

Waters ×121

* Residue conservation analysis

PDB id:

2w3k

Name:

Hydrolase

Title:

Crystal structure of fxa in complex with 4,4-disubstituted pyrrolidine-1,2-dicarboxamide inhibitor 1

Structure:

Coagulation factor x, heavy chain. Chain: a. Fragment: heavy chain, residues 235-468. Synonym: activated factor xa, stuart factor, stuart-prower factor. Engineered: yes. Coagulation factor x, light chain. Chain: b. Fragment: light chain, residues 128-178. Synonym: activated factor xa, stuart factor, stuart-prower factor.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Resolution:

2.05Å R-factor: 0.211 R-free: 0.255

Authors:

E.Zhang,I.Mochalkin,A.Casimiro-Garcia,C.A.Van Huis

Key ref:

C.A.Van Huis et al. (2009). Exploration of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides as potent, orally active Factor Xa inhibitors with extended duration of action. Bioorg Med Chem Lett, 17, 2501-2511. PubMed id: 19231206

Date:

12-Nov-08 Release date: 07-Apr-09

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 234 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.

Bioorg Med Chem Lett 17:2501-2511 (2009)

PubMed id: 19231206

Exploration of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides as potent, orally active Factor Xa inhibitors with extended duration of action.

C.A.Van Huis, A.Casimiro-Garcia, C.F.Bigge, W.L.Cody, D.A.Dudley, K.J.Filipski, R.J.Heemstra, J.T.Kohrt, R.J.Leadley, L.S.Narasimhan, T.McClanahan, I.Mochalkin, M.Pamment, J.T.Peterson, V.Sahasrabudhe, R.P.Schaum, J.J.Edmunds.

ABSTRACT

Aiming to improve upon previously disclosed Factor Xa inhibitors, a series of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides were explored with the intent of increasing the projected human half-life versus 5 (projected human t(1/2)=6 h). A stereospecific route to compounds containing a 4-aryl-4-hydroxypyrrolidine scaffold was developed, resulting in several compounds that demonstrated an increase in the half-life as well as an increase in the in vitro potency compared to 5. Reported herein is the discovery of 26, containing a (2R,4S)-4-hydroxy-4-(2,4-difluorophenyl)-pyrrolidine scaffold, which is a selective, orally bioavailable, efficacious Factor Xa inhibitor that appears suitable for a once-daily dosing (projected human t(1/2)=23 h).