Strategies and progress towards the ideal orally active thrombin inhibitor

Thrombin plays a key role in the control of thrombus formation, for which r eason its inhibition has become a target for new antithrombotics. Important issues in the profile of the ideal thrombin inhibitor are: potency, select ivity, oral bioavailability, half-life in the circulatory system and safety . Although many potent direct inhibitors of thrombin have been discovered, most of these inhibitors lack sufficient oral bioavailability. This is ofte n associated with the presence of highly basic functionalities such as guan idine or amidine. These basic functionalities in the P-1 moiety are preferr ed by thrombin and are present in the first generation of thrombin inhibito rs. Recently, several orally active direct thrombin inhibitors have been di sclosed. Most of these inhibitors originate from leads of the first generat ion. Two major optimization strategies could be identified to further impro ve these leads: A: maintain the highly basic P-1 moiety and compensate its negative effects, and B: reduce the basicity of the P-1 moiety and compensa te for the decrease in inhibitory activity. The progress made using these s trategies is evaluated. In addition, screening large sets of compounds yiel ded new structures that provide useful starting points for optimization. Th e optimization strategy used to convert leads from screening into potent or ally active thrombin inhibitors is also be evaluated.Thrombin plays a key r ole in the control of thrombus formation, for which reason its inhibition h as become a target for new antithrombotics. Important issues in the profile of the ideal thrombin inhibitor are: potency, selectivity, oral bioavailab ility, half-life in the circulatory system and safety. Although many potent direct inhibitors of thrombin have been discovered, most of these inhibito rs lack sufficient oral bioavailability. This is often associated with the presence of highly basic functionalities such as guanidine or amidine. Thes e basic functionalities in the P-1 moiety are preferred by thrombin and are present in the first generation of thrombin inhibitors. Recently, several orally active direct thrombin inhibitors have been disclosed. Most of these inhibitors originate from leads of the first generation. Two major optimiz ation strategies could be identified to further improve these leads: A: mai ntain the highly basic P-1 moiety and compensate its negative effects, and B: reduce the basicity of the P-1 moiety and compensate for the decrease in inhibitory activity. The progress made using these strategies is evaluated . In addition, screening large sets of compounds yielded new structures tha t provide useful starting points for optimization. The optimization strateg y used to convert leads from screening into potent orally active thrombin i nhibitors is also be evaluated.