NOVEL INHIBITORS OF COAGULATION PROTEASES

WE WILL DEVELOP NOVEL PEPTIDYL DIFLUOROKETOAMIDES (DFK'S) OF THERAPEUTIC UTILITY TO INTERRUPT SEVERE LIFE-THREATENING SEPTIC SHOCK, THROMBOTIC AND RELATED DISEASES IN WHICH THE INTRAVASCULAR ACTIVATION OF THE COAGULATION PROTEASE PATHWAYS PLAY A SIGNIFICANT PATHOGENETIC ROLE. REVERSIBLE INHIBITORS ARE PREDICTED TO BE OF THERAPEUTIC VALUE BASED ON THE SPECIFIC TIGHT-BINDING INHIBITION OF THE SERINE PROTEASE CATALYTIC SITES OF SELECTED COAGULATION PROTEASES, E. G. TISSUE FACTOR:FACTOR VIIA (TF:VIIA), FACTOR XA, THROMBIN AND KALLIKREIN. IN PHASE I, A SYNTHETIC ROUTE TO NOVEL ARGININE CONTAINING DIFLUOROKETOAMIDES WILL BE WORKED OUT. REVERSIBLE INHIBITORS BASED ON THE KNOWN THROMBIN INHIBITOR, PPACK, WILL BE PREPARED. THESE COMPOUNDS WILL BE ANALYZED FOR THEIR FUNCTIONAL ENZYMATIC SPECIFICITY AND COMPARED TO OTHER WELL CHARACTERIZED THROMBIN INHIBITORS. IN PHASE II, NEW DFK'S WILL BE SYNTHESIZED AND EVALUATED AS SPECIFIC INHIBITORS FOR TF:VIIA, FACTOR XA, THROMBIN AND KALLIKREIN. SUBSEQUENTLY, THE THERAPEUTIC EFFICACY OF SELECTED COMPOUNDS WELL BE EVALUATED IN VIVO IN SELECTED ANIMAL MODELS FOR SEPTIC SHOCK AND TF INITIATED COAGULATION.