Author/Authors :
Michael S. South، نويسنده , , Brenda L. Case، نويسنده , , Rhonda S. Wood، نويسنده , , Darin E. Jones، نويسنده , , Michael J. Hayes، نويسنده , , Thomas J. Girard، نويسنده , , Rhonda M. Lachance، نويسنده , , Nancy S. Nicholson، نويسنده , , Michael Clare، نويسنده , , Anna M. Stevens، نويسنده , , Roderick A. Stegeman، نويسنده , , William C. Stallings، نويسنده , , Ravi G. Kurumbail، نويسنده , , John J. Parlow، نويسنده ,
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.
