Lead Optimization to Advance Protease-Activated Receptor-1 Antagonists in Early Discovery.

Vorapaxar is an approved drug for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Subsequent to the discovery of Vorapaxar, medicinal chemistry efforts were continued to identify structurally differentiated leads. Toward this goal, extensive structure-activity relationship studies using a C-ring-truncated version of Vorapaxar culminated in the discovery of three leads, represented as , , and .

Evaluation of two blood microsampling approaches for drug discovery PK studies in rats.

Background: Serial sampling in discovery rat PK studies could be performed via capillary microsampling (CMS) of blood or by using the Mitra™ device to collect dried blood samples.

Results: Blood CMS results were compared with Mitra sampling results for four test compounds dosed in rat PK studies. The PK profiles obtained from CMS sampling were found to be very similar to those obtained from the Mitra sampling.