PDBsum entry 4ty7

Hydrolase/hydrolase inhibitor

PDB id: 4ty7

Contents

Protein chain

238 a.a.

Ligands

39F

SO4 ×2

EDO ×7

Waters ×221

PDB id:

4ty7

Name:

Hydrolase/hydrolase inhibitor

Title:

Factor xia in complex with the inhibitor (2s)-6-amino-n-{(1s)-1-[4-(3- amino-2h-indazol-6-yl)-5-chloro-1h-imidazol-2-yl]-2-phenylethyl}-2- ethylhexanamide

Structure:

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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: f11. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.09Å R-factor: 0.180 R-free: 0.206

Authors:

A.Wei

Key ref:

J.J.Hangeland et al. (2014). Phenylimidazoles as potent and selective inhibitors of coagulation factor XIa with in vivo antithrombotic activity. J Med Chem, 57, 9915-9932. PubMed id: 25405503 DOI: 10.1021/jm5010607

Date:

08-Jul-14 Release date: 03-Dec-14

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/jm5010607

J Med Chem 57:9915-9932 (2014)

PubMed id: 25405503

Phenylimidazoles as potent and selective inhibitors of coagulation factor XIa with in vivo antithrombotic activity.

J.J.Hangeland, T.J.Friends, K.A.Rossi, J.M.Smallheer, C.Wang, Z.Sun, J.R.Corte, T.Fang, P.C.Wong, A.R.Rendina, F.A.Barbera, J.M.Bozarth, J.M.Luettgen, C.A.Watson, G.Zhang, A.Wei, V.Ramamurthy, P.E.Morin, G.S.Bisacchi, S.Subramaniam, P.Arunachalam, A.Mathur, D.A.Seiffert, R.R.Wexler, M.L.Quan.

ABSTRACT

Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.