PDBsum entry 4na8

Hydrolase/hydrolase inhibitor

PDB id: 4na8

Contents

Protein chain

238 a.a.

Ligands

1T6

SO4

EDO ×2

Waters ×100

PDB id:

4na8

Name:

Hydrolase/hydrolase inhibitor

Title:

Factor xia in complex with the inhibitor 5-aminocarbonyl-2-[3-[(2s, 4r)-6-carbamimidoyl-4-methyl-4-phenyl-2,3-dihydro-1h-quinolin-2- yl]phenyl]benzoic acid

Structure:

Coagulation factor xi. Chain: a. Synonym: fxi, plasma thromboplastin antecedent, pta, coagulation factor xia heavy chain, coagulation factor xia light chain. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: f11. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.30Å R-factor: 0.231 R-free: 0.271

Authors:

A.Wei

Key ref:

M.L.Quan et al. (2014). Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors. J Med Chem, 57, 955-969. PubMed id: 24405333 DOI: 10.1021/jm401670x

Date:

21-Oct-13 Release date: 12-Feb-14

Protein chain

P03951  (FA11_HUMAN) -  Coagulation factor XI from Homo sapiens

Seq: 625 a.a.

Struc: 238 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.21.27 - coagulation factor XIa.
• Reaction: Selective cleavage of Arg-|-Ala and Arg-|-Val bonds in factor IX to form factor IXa.

DOI no: 10.1021/jm401670x

J Med Chem 57:955-969 (2014)

PubMed id: 24405333

Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors.

M.L.Quan, P.C.Wong, C.Wang, F.Woerner, J.M.Smallheer, F.A.Barbera, J.M.Bozarth, R.L.Brown, M.R.Harpel, J.M.Luettgen, P.E.Morin, T.Peterson, V.Ramamurthy, A.R.Rendina, K.A.Rossi, C.A.Watson, A.Wei, G.Zhang, D.Seiffert, R.R.Wexler.

ABSTRACT

Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound 1 was identified as a potent and selective tool compound for proof of concept studies. It exhibited excellent antithrombotic efficacy in rabbit thrombosis models and did not prolong bleeding times. This demonstrates proof of concept for the FXIa mechanism in animal models with a reversible, small molecule inhibitor.