Structure-activity relationships of new NAPAP-analogs

Several new analogs of the known thrombin inhibitor NAPAP were synthesized, in which the P2 glycine residue was substituted by natural and unnatural a mino acids. The thrombin inhibitory potency was comparable to that of NAPAP . Several of the compounds had inhibition constants lower than 10 nM and a very high selectivity compared to trypsin, factor X-a and plasmin. In addit ion, analogs were prepared by alkylation of the N-alpha-atom of the 4-amidi nophenylalanine in P1 position, which showed a more than 10-fold lower thro mbin inhibition. Furthermore, azaglycine was introduced instead of P2 glyci ne. For most of the inhibitors similar fast elimination rates were seen in rats after intravenous dosing, as found previously for NAPAP. Only some com pounds, which contained a second basic group showed a slightly decreased cu mulative biliary clearance.