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Improvement of the synthesis and pharmacokinetic properties of chromenotriazolopyrimidine MDM2-p53 protein-protein inhibitors |
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| Authors: | Beck Hilary P DeGraffenreid Michael Fox Brian Allen John G Rew Yosup Schneider Stephen Saiki Anne Y Yu Dongyin Oliner Jonathan D Salyers Kevin Ye Qiuping Olson Steven |
| Affiliation: | a Chemistry Research & Discovery, Amgen Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA b Chemistry Research & Discovery, Amgen Inc., One Amgen Center Drive Thousand Oaks, CA 91320, USA c Chemistry Research & Discovery, Amgen Inc., 360 Binney Street Cambridge, MA 02142, USA d Oncology Research, Amgen Inc., One Amgen Center Drive Thousand Oaks, CA 91320, USA e PKDM, Amgen Inc., One Amgen Center Drive Thousand Oaks, CA 91320, USA f PKDM, Amgen Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA |
| Abstract: | 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. |
| Keywords: | Oncology Protein-protein interaction Pharmacokinetics |
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