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Reversible, orally available ADP receptor (P2Y12) antagonists Part I: Hit to lead process
Imadul Islam1, Shendong Yuan2, Robert G Wei2
1Medical Core Facility and Research Platforms, King Abdullah International Medical Research Center/King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs, Riyadh 11426, Saudi Arabia; Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Abstract:
A hit to lead process to identify reversible, orally available ADP receptor (P2Y12) 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 (KB = 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.
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