Abstract for PubMed entry 12824026

Title		Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex.
Authors		M.S.South, B.L.Case, R.S.Wood, D.E.Jones, M.J.Hayes, T.J.Girard, R.M.Lachance, N.S.Nicholson, M.Clare, A.M.Stevens, R.A.Stegeman, W.C.Stallings, R.G.Kurumbail, J.J.Parlow.
Ref.		Bioorg Med Chem Lett, 2003, 13, 2319-2325.
PubMed id		12824026
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 P(2) 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 P(1) and P(3) moieties, which led to synthesis pyrazinone 23. Compound 23 exhibited 16 nM IC(50) against TF/VIIa with >6250x 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.