Bioisosterism has been a powerful tool in medicinal chemistry that affects compound potency, selectivity, and metabolism. Acyl piperizine and phenyl ether share similar shape, conformation, and hydrogen-bond acceptor but have dramatically different physiochemical properties. By replacing acyl piperizine with phenyl ether, we may alter a molecule's metabolism without disrupting its key interactions with receptor. Such isosteric replacement was applied to GDC-0068, a potent and selective Akt inhibitor currently in clinical development for treating cancer.  A novel potent Akt inhibitor with clogD shifted by two units and improved metabolic stability was discovered based on the phenyl ether scaffold.

Isosteric replacement of acyl piperizine with phenyl ether: Improving metabolic stability of GDC-0068 class of Akt inhibitors

248th National Meeting (2014)

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