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Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2-p53 Interaction.

ABSTRACT: Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Compound 23 exhibits excellent pharmacokinetic properties and substantial in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse model.

SUBMITTER: Yu M

PROVIDER: S-EPMC4137378 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2-p53 Interaction.

Yu Ming M Wang Yingcai Y Zhu Jiang J Bartberger Michael D MD Canon Jude J Chen Ada A Chow David D Eksterowicz John J Fox Brian B Fu Jiasheng J Gribble Michael M Huang Xin X Li Zhihong Z Liu Jiwen Jim JJ Lo Mei-Chu MC McMinn Dustin D Oliner Jonathan D JD Osgood Tao T Rew Yosup Y Saiki Anne Y AY Shaffer Paul P Yan Xuelei X Ye Qiuping Q Yu Dongyin D Zhao Xiaoning X Zhou Jing J Olson Steven H SH Medina Julio C JC Sun Daqing D

ACS medicinal chemistry letters 20140630 8

Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Compound 23 exhibits excellent pharmacokinetic properties and substantial in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse model. ...[more]

PMID: 25147610

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Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction.

Project description:We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a K(i) of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model.

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Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development.

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