Reversible, orally available ADP receptor (P2Y12) antagonists Part I: Hit to lead process

Abstract 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.