Discovery of diarylurea P2Y1 antagonists with improved aqueous solubility

Preclinical data suggests that P2Y(1) antagonists, such as diarylurea compound 1, may provide antithrombotic efficacy similar to P2Y(12) antagonists and may have the potential of providing reduced bleeding liabilities. This manuscript describes a series of diarylureas bearing solublizing amine side chains as potent P2Y(1) antagonists. Among them, compounds 2l and 3h had improved aqueous solubility and maintained antiplatelet activity compared with compound 1. Compound 2l was moderately efficacious in both rat and rabbit thrombosis models and had a moderate prolongation of bleeding time in rats similar to that of compound 1. (C) 2013 Elsevier Ltd. All rights reserved.