4 research outputs found
Small-scale fisheries in the context of traditional post-harvest practice and the quest for food and nutritional security in Nigeria
Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2–p53 Interaction
Continued optimization of the N-substituent
in the piperidinone
series provided potent piperidinone–pyridine inhibitors <b>6</b>, <b>7</b>, <b>14</b>, and <b>15</b> with
improved pharmacokinetic properties in rats. Reducing structure complexity
of the <i>N</i>-alkyl substituent led to the discovery of <b>23</b>, a potent and simplified inhibitor of MDM2. Compound <b>23</b> exhibits excellent pharmacokinetic properties and substantial
in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse
model
Discovery of AMG 232, a Potent, Selective, and Orally Bioavailable MDM2–p53 Inhibitor in Clinical Development
We
recently reported the discovery of AM-8553 (<b>1</b>),
a potent and selective piperidinone inhibitor of the MDM2–p53
interaction. Continued research investigation of the <i>N</i>-alkyl substituent of this series, focused in particular on a previously
underutilized interaction in a shallow cleft on the MDM2 surface,
led to the discovery of a one-carbon tethered sulfone which gave rise
to substantial improvements in biochemical and cellular potency. Further
investigation produced AMG 232 (<b>2</b>), which is currently
being evaluated in human clinical trials for the treatment of cancer.
Compound <b>2</b> is an extremely potent MDM2 inhibitor (SPR <i>K</i><sub>D</sub> = 0.045 nM, SJSA-1 EdU IC<sub>50</sub> = 9.1
nM), with remarkable pharmacokinetic properties and in vivo antitumor
activity in the SJSA-1 osteosarcoma xenograft model (ED<sub>50</sub> = 9.1 mg/kg)