PDBsum entry 4ng9

Hydrolase/hydrolase inhibitor

PDB id: 4ng9

Contents

Protein chains

250 a.a.

54 a.a.

Ligands

2KE

SO4 ×5

GOL

Metals

_CA

Waters ×257

PDB id:

4ng9

Name:

Hydrolase/hydrolase inhibitor

Title:

Factor viia in complex with the inhibitor (2r)-2-[(1-aminoisoquinolin- 6-yl)amino]-2-[3-ethoxy-4-(propan-2-yloxy)phenyl]-n-(3- sulfamoylbenzyl)ethanamide

Structure:

Factor viia (heavy chain). Chain: h. Fragment: unp residues 213-466. Synonym: factor vii heavy chain, activated factor viia heavy chain. Engineered: yes. Factor viia (light chain). Chain: l. Fragment: uknp residues 150-204. Synonym: factor viia light chain.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Gene: f7. Expression_system_taxid: 10029

Resolution:

2.20Å R-factor: 0.187 R-free: 0.222

Authors:

A.Wei,R.Anumula

Key ref:

X.Zhang et al. (2014). Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors. ACS Med Chem Lett, 5, 188-192. PubMed id: 24900796

Date:

01-Nov-13 Release date: 08-Jan-14

Protein chain

P08709  (FA7_HUMAN) -  Coagulation factor VII from Homo sapiens

Seq: 466 a.a.

Struc: 250 a.a.

Protein chain

P08709  (FA7_HUMAN) -  Coagulation factor VII from Homo sapiens

Seq: 466 a.a.

Struc: 54 a.a.

Enzyme reactions

• Enzyme class: Chains H, L: E.C.3.4.21.21 - coagulation factor VIIa.
• Reaction: Hydrolyzes one Arg-|-Ile bond in factor X to form factor Xa.

ACS Med Chem Lett 5:188-192 (2014)

PubMed id: 24900796

Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors.

X.Zhang, W.Jiang, S.Jacutin-Porte, P.W.Glunz, Y.Zou, X.Cheng, A.H.Nirschl, N.R.Wurtz, J.M.Luettgen, A.R.Rendina, G.Luo, T.M.Harper, A.Wei, R.Anumula, D.L.Cheney, R.M.Knabb, P.C.Wong, R.R.Wexler, E.S.Priestley.

ABSTRACT

Inhibitors of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising novel anticoagulants that show excellent efficacy and minimal bleeding in preclinical models. On the basis of a zwitterionic phenylglycine acylsulfonamide 1, a phenylglycine benzylamide 2 was shown to possess improved permeability and oral bioavailability. Optimization of the benzylamide, guided by X-ray crystallography, led to a potent TF-FVIIa inhibitor 18i with promising oral bioavailability, but promiscuous activity in an in vitro safety panel of receptors and enzymes. Introducing an acid on the pyrrolidine ring, guided by molecular modeling, resulted in highly potent, selective, and efficacious TF-FVIIa inhibitors with clean in vitro safety profile. The pyrrolidine acid 20 showed a moderate clearance, low volume of distribution, and a short t 1/2 in dog PK studies.