Unexpected enhancement of thrombin inhibitor potency with o-aminoalkylbenzylamides in the P1 position.

Thrombin inhibitors incorporating o-aminoalkylbenzylamides in the P1 position were designed, synthesized and found to have enhanced potency and selectivity in several different structural classes. X-ray crystallographic analysis of compound 24 bound in the alpha-thrombin-hirugen complex provides an explanation for these unanticipated results.

Low molecular weight thrombin inhibitors with excellent potency, metabolic stability, and oral bioavailability.

Modification of lead compound 1 by reducing lipophilicity in the P3 group produced a series of low molecular weight thrombin inhibitors with excellent potency in functional assays, metabolic stability, and oral bioavailability. These modifications led to the identification of two optimized compounds, 14 and 16.