PDBsum entry 5e2o

Hydrolase/hydrolase inhibitor

PDB id: 5e2o

Contents

Protein chain

238 a.a.

Ligands

5JM

SO4 ×2

EDO ×9

Waters ×211

PDB id:

5e2o

Name:

Hydrolase/hydrolase inhibitor

Title:

Factor xia in complex with the inhibitor 4-[(n-{(2e)-3-[5-chloro-2- (1h-tetrazol-1-yl)phenyl]prop-2-enoyl}-l-phenylalanyl)amino]benzoic acid

Structure:

Coagulation factor xia light chain. Chain: a. 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: 562.

Resolution:

2.08Å R-factor: 0.186 R-free: 0.214

Authors:

A.Wei

Key ref:

L.M.Smith et al. (2016). Novel phenylalanine derived diamides as Factor XIa inhibitors. Bioorg Med Chem Lett, 26, 472-478. PubMed id: 26704266 DOI: 10.1016/j.bmcl.2015.11.089

Date:

01-Oct-15 Release date: 09-Dec-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: 10.1016/j.bmcl.2015.11.089

Bioorg Med Chem Lett 26:472-478 (2016)

PubMed id: 26704266

Novel phenylalanine derived diamides as Factor XIa inhibitors.

L.M.Smith, M.J.Orwat, Z.Hu, W.Han, C.Wang, K.A.Rossi, P.J.Gilligan, K.B.Pabbisetty, H.Osuna, J.R.Corte, A.R.Rendina, J.M.Luettgen, P.C.Wong, R.Narayanan, T.W.Harper, J.M.Bozarth, E.J.Crain, A.Wei, V.Ramamurthy, P.E.Morin, B.Xin, J.Zheng, D.A.Seiffert, M.L.Quan, P.Y.Lam, R.R.Wexler, D.J.Pinto.

ABSTRACT

The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our clotting assay (aPPT), and high selectivity against a panel of relevant serine proteases as exemplified by compound 21. Compound 21 demonstrated good in vivo efficacy (EC50=2.8μM) in the rabbit electrically induced carotid arterial thrombosis model (ECAT).