@article{6029db44025245a6a6f7bad3038ae849,
title = "Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex",
abstract = "Structure-based drug design coupled with polymer-assisted solution-phase library synthesis was utilized to develop a series of pyrazinone inhibitors of the tissue factor/Factor VIIa complex. The crystal structure of a tri-peptide ketothiazole complexed with TF/VIIa was utilized in a docking experiment that identified a benzyl-substituted pyrazinone as a P2 surrogate for the tri-peptide. A 5-step PASP library synthesis of these aryl-substituted pyrazinones was developed. The sequence allows for attachment of a variety of P1 and P3 moieties, which led to synthesis pyrazinone 23. Compound 23 exhibited 16 nM IC50 against TF/VIIa with >6250× selectivity versus Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for pre-clinical intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a primate model of thrombosis.",
author = "South, {Michael S.} and Case, {Brenda L.} and Wood, {Rhonda S.} and Jones, {Darin E.} and Hayes, {Michael J.} and Girard, {Thomas J.} and Lachance, {Rhonda M.} and Nicholson, {Nancy S.} and Michael Clare and Stevens, {Anna M.} and Stegeman, {Roderick A.} and Stallings, {William C.} and Kurumbail, {Ravi G.} and Parlow, {John J.}",
note = "Funding Information: We thank Dr. Huey Shieh for some of the early crystallographic refinements of the TF-VIIa structure. Diffraction data of inhibitor complexes with TF-VIIa were collected at beamline 17-ID in the facilities of the Industrial Macromolecular Crystallography Association Collaborative Access Team (IMCA-CAT) at the Advanced Photon Source. IMCA-CAT facilities are supported by the corporate members of the IMCA and through a contract with Illinois Institute of Technology (IIT), executed through the IIT's Center for Synchrotron Radiation Research and Instrumentation. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. W-31-109-Eng-38.",
year = "2003",
month = jul,
day = "21",
doi = "10.1016/S0960-894X(03)00410-4",
language = "English",
volume = "13",
pages = "2319--2325",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
number = "14",
}