Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors

A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by <b>21</b> has been developed from the initial lead <b>1</b>. Research focused on optimization of a crucial HDM2 Trp23–ligand interaction led to the identification of 2-(trifluoromethyl)­thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors <b>3</b>, <b>10</b>, and <b>21</b> is described