2 research outputs found
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
MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology
The
emergence and evolution of new immunological cancer therapies has
sparked a rapidly growing interest in discovering novel pathways to
treat cancer. Toward this aim, a novel series of pyrrolidine derivatives
(compound <b>5</b>) were identified as potent inhibitors of
ERK1/2 with excellent kinase selectivity and dual mechanism of action
but suffered from poor pharmacokinetics (PK). The challenge of PK
was overcome by the discovery of a novel 3(<i>S</i>)-thiomethyl
pyrrolidine analog <b>7</b>. Lead optimization through focused
structure–activity relationship led to the discovery of a clinical
candidate <b>MK-8353</b> suitable for twice daily oral dosing
as a potential new cancer therapeutic