PDBsum entry 4y8x

Hydrolase/hydrolase inhibitor

PDB id: 4y8x

Contents

Protein chain

238 a.a.

Ligands

4GR

SO4 ×2

EDO ×9

Waters ×215

PDB id:

4y8x

Name:

Hydrolase/hydrolase inhibitor

Title:

Factor xia in complex with the inhibitor methyl (4-{4-chloro-2-[(1s)- 1-({(2e)-3-[5-chloro-2-(1h-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)- 2-phenylethyl]-1h-imidazol-5-yl}phenyl)carbamate

Structure:

Coagulation factor xia. Chain: a. Fragment: light chain (unp residues 388-625). Synonym: fxi, plasma thromboplastin antecedent, pta. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: f11. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.90Å R-factor: 0.158 R-free: 0.164

Authors:

S.Sheriff

Key ref:

Z.Hu et al. (2015). Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1H)-one as the P2' Moiety. Acs Med Chem Lett, 6, 590-595. PubMed id: 26005539 DOI: 10.1021/acsmedchemlett.5b00066

Date:

16-Feb-15 Release date: 27-May-15

Protein chain

P03951  (FA11_HUMAN) -  Coagulation factor XI from Homo sapiens

Seq: 625 a.a.

Struc: 238 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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/acsmedchemlett.5b00066

Acs Med Chem Lett 6:590-595 (2015)

PubMed id: 26005539

Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1H)-one as the P2' Moiety.

Z.Hu, P.C.Wong, P.J.Gilligan, W.Han, K.B.Pabbisetty, J.M.Bozarth, E.J.Crain, T.Harper, J.M.Luettgen, J.E.Myers, V.Ramamurthy, K.A.Rossi, S.Sheriff, C.A.Watson, A.Wei, J.J.Zheng, D.A.Seiffert, R.R.Wexler, M.L.Quan.

ABSTRACT

Structure-activity relationship optimization of phenylalanine P1' and P2' regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2' group enhanced FXIa affinity and metabolic stability. Incorporation of an N-methyl piperazine amide group to replace the phenylalanine improved both FXIa potency and aqueous solubility. Combination of the optimization led to the discovery of FXIa inhibitor 13 with a FXIa K i of 0.04 nM and an aPTT EC2x of 1.0 μM. Dose-dependent efficacy (EC50 of 0.53 μM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation.