期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 28, 期 9, 页码 1459-1463出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2018.03.090
关键词
Antiplatelet therapy; ADP; P2Y(12) antagonists; HTS; Parallel synthesis
A hit to lead process to identify reversible, orally available ADP receptor (P2Y(12)) antagonists lead compounds is described. High throughput screening afforded 1. Optimization of 1, using parallel synthesis methods, a methyl scan to identify promising regions for optimization, and exploratory SAR on these regions, provided 22 and 23. Compound 23 is an orally available, competitive reversible antagonist (K-B = 94 nM for inhibition of ADP-induced platelet aggregation). It exhibits high metabolic stability in human, rat and dog liver microsomes and is orally absorbed. Although plasma level after oral dosing of 22 and 23 to rats is low, reasonable levels were achieved to merit extensive lead optimization of this structural class. (C) 2018 Elsevier Ltd. All rights reserved.
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