Discovery of AZD8165-a clinical candidate from a novel series of neutral thrombin inhibitors

A novel series of neutral thrombin inhibitors has been developed using a selection process based on docking experiments and property calculations and predictions. This work resulted in the identification of the highly potent thrombin inhibitor compound 85 (K-i = 300 pM) and the corresponding propionate prodrug 5 (AZD8165) as a candidate for clinical evaluation in the treatment of thrombosis and related diseases. AZD8165 was found to be safe and well tolerated and delivered the expected pharmacological response in a phase I trial in healthy male volunteers.