Robert Theodore Shuman

N-substituted glycines as replacements for proline in tripeptide aldehyde thrombin inhibitors

Abstract We have prepared a series of tripeptide arginine aldehydes in which the P2 proline has been replaced with a variety of N -substituted glycines. The effects of these modifications on thrombin inhibitory potency and serine protease selectivity were evaluated.

Development of an orally active tripeptide arginal thrombin inhibitor.

The parenteral agent efegatran was chosen for clinical evaluation after extensive SAR studies and subsequent collaborations with the HIDR. It was studied extensively in Phase 1 and Phase 2 clinical trials to determine if it could provide superior benefits to heparin for cardiovascular patients with unstable angina or thrombolysis during acute myocardial infarction. Analysis of data from Phase 2 clinical trials demonstrated that efegatran exhibited equivalent efficacy to heparin. As a consequence further development with this parenteral agent was discontinued.