Improvement of the synthesis and pharmacokinetic properties of chromenotriazolopyrimidine MDM2-p53 protein-protein inhibitors.
Human murine double minute 2 (MDM2) is a negative regulator of p53, which plays an important role in cell cycle and apoptosis. We report several optimizations to the synthesis of the chromenotriazolopyrimidine series of MDM2-p53 protein-protein interaction inhibitors. Additionally, the in vitro and in vivo stability, pharmacokinetic properties and solubility were improved through N-substitution.
Chemistry Research & Discovery, Amgen Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA. hbeck@amgen.com
Hilary P
HP
Beck
Michael
M
DeGraffenreid
Brian
B
Fox
John G
JG
Allen
Yosup
Y
Rew
Stephen
S
Schneider
Anne Y
AY
Saiki
Dongyin
D
Yu
Jonathan D
JD
Oliner
Kevin
K
Salyers
Qiuping
Q
Ye
Steven
S
Olson
D000818:Animals; D004355:Drug Stability; D006801:Humans; D007260:Infusion Pumps; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2