DISCOVERY AND DEVELOPMENT OF THE NOVEL POTENT ORALLY-ACTIVE THROMBIN INHIBITOR N-(9-HYDROXY-9-FLUORENECARBOXY)PROLYL TRANS-4-AMINOCYCLOHEXYLMETHYL AMIDE (L-372,460) - COAPPLICATION OF STRUCTURE-BASED DESIGN AND RAPID MULTIPLE ANALOG SYNTHESIS ON SOLID SUPPORT

Early studies in these laboratories of peptidomimetic structures conta ining a basic P-1 moiety led to the highly potent and selective thromb in inhibitors 2 (K-i = 5.0 nM) and 3 (K-i = 0.1 nM). However, neither attains significant blood levels upon oral administration to rats and dogs. With the aim of improving pharmacokinetic properties tia a more diverse database, we devised a resin-based route for the synthesis of analogues of these structures in which the P-3 residue is replaced wit h a range of lipophilic carboxylic amides. Assembly proceeds from the common P-2-P-1 template 7 linked via an acid-labile carbamate to a pol ystyrene support. Application of the methodology in a repetitive fashi on afforded several interesting analogues out of a collection of some 200 compounds. Among the most potent of the group, N-(9-hydroxy-9-fluo renecarboxy)prolyl trans-4-aminocyclohexylmethyl amide (L-372,460 8, K -i = 1.5 nM), in addition to being fully efficacious in a rat model of arterial thrombosis at an infusion rate of 10 mu g/kg/min, exhibits o ral bioavailability of 74% in dogs, and oral bioavailability of 39% in monkeys with a serum half-life of just under 4 h. On the basis of its favorable biological properties, inhibitor 8 has been subject to furt her evaluation as a possible treatment for thrombogenic disorders.