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

Autor: Yu M; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Wang Y; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Zhu J; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Bartberger MD; Departments of Therapeutic Discovery and Oncology Research, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States., Canon J; Departments of Therapeutic Discovery and Oncology Research, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States., Chen A; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Chow D; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Eksterowicz J; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Fox B; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Fu J; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Gribble M; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Huang X; Department of Therapeutic Discovery, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States., Li Z; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Liu JJ; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Lo MC; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., McMinn D; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Oliner JD; Departments of Therapeutic Discovery and Oncology Research, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States., Osgood T; Departments of Therapeutic Discovery and Oncology Research, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States., Rew Y; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Saiki AY; Departments of Therapeutic Discovery and Oncology Research, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States., Shaffer P; Department of Therapeutic Discovery, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States., Yan X; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Ye Q; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Yu D; Departments of Therapeutic Discovery and Oncology Research, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States., Zhao X; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Zhou J; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Olson SH; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Medina JC; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States., Sun D; Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2014 Jun 30; Vol. 5 (8), pp. 894-9. Date of Electronic Publication: 2014 Jun 30 (Print Publication: 2014).
DOI: 10.1021/ml500142b
Abstrakt: 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.
Databáze: MEDLINE