AMG232 - CAS 1352066-68-2
Catalog number: 1352066-68-2
Category: Inhibitor
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MDM-2, p53
AMG232 is an extremely potent MDM2 inhibitor with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg). AMG232 is currently under clinical development.
Solid powder
AMG-232; AMG 232.
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1.Optimization beyond AMG 232: discovery and SAR of sulfonamides on a piperidinone scaffold as potent inhibitors of the MDM2-p53 protein-protein interaction.
Wang Y;Zhu J;Liu JJ;Chen X;Mihalic J;Deignan J;Yu M;Sun D;Kayser F;McGee LR;Lo MC;Chen A;Zhou J;Ye Q;Huang X;Long AM;Yakowec P;Oliner JD;Olson SH;Medina JC Bioorg Med Chem Lett. 2014 Aug 15;24(16):3782-5. doi: 10.1016/j.bmcl.2014.06.073. Epub 2014 Jul 1.
We recently reported on the discovery of AMG 232, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. AMG 232 is being evaluated in human clinical trials for cancer. Continued exploration of the N-alkyl substituent of this series, in an effort to optimize interactions with the MDM2 glycine-58 shelf region, led to the discovery of sulfonamides such as compounds 31 and 38 that have similar potency, hepatocyte stability and rat pharmacokinetic properties to AMG 232.
2.Pharmacokinetics and metabolism of AMG 232, a novel orally bioavailable inhibitor of the MDM2-p53 interaction, in rats, dogs and monkeys: in vitro-in vivo correlation.
Ye Q;Jiang M;Huang WT;Ling Y;Olson SH;Sun D;Xu G;Yan X;Wong BK;Jin L Xenobiotica. 2015;45(8):681-92. doi: 10.3109/00498254.2015.1010632. Epub 2015 Mar 23.
1. AMG 232 is a novel inhibitor of the p53-MDM2 protein-protein interaction currently in Phase I clinical trials for multiple tumor indications. The objectives of the investigations reported in this article were to characterize the pharmacokinetic and drug metabolism properties of AMG 232 in pre-clinical species in vivo and in vitro, and in humans in vitro, and to predict its pharmacokinetics in humans through integrating PKDM data. 2. AMG 232 exhibited low clearance (<0.25 × Qh) and moderate to high oral bioavailability in mice, rats and monkeys (>42%), but high clearance (0.74 × Qh) and low oral exposure in dogs (18%). 3. Biotransformation was the major route of elimination of AMG 232 in rats, with only 7% of intravenously administered (14)C-labeled AMG 232 recovered as parent molecule in bile. The major metabolite was an acyl glucuronide as measured by in vivo rat studies and in vitro hepatocyte incubations in multiple species. 4. The in vitro-in vivo correlation of AMG 232 clearance was within 2-fold in pre-clinical species using hepatocytes. AMG 232 was predicted to exhibit low clearance, high volume distribution and long half-life in humans. The predictions are consistent with the preliminary human pharmacokinetic parameters of AMG 232 in clinical trials.
3.Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development.
Sun D;Li Z;Rew Y;Gribble M;Bartberger MD;Beck HP;Canon J;Chen A;Chen X;Chow D;Deignan J;Duquette J;Eksterowicz J;Fisher B;Fox BM;Fu J;Gonzalez AZ;Gonzalez-Lopez De Turiso F;Houze JB;Huang X;Jiang M;Jin L;Kayser F;Liu JJ;Lo MC;Long AM;Lucas B;McGee LR;McIntosh J;Mihalic J;Oliner JD;Osgood T;Peterson ML;Roveto P;Saiki AY;Shaffer P;Toteva M;Wang Y;Wang YC;Wortman S;Yakowec P;Yan X;Ye Q;Yu D;Yu M;Zhao X;Zhou J;Zhu J;Olson SH;Medina JC J Med Chem. 2014 Feb 27;57(4):1454-72. doi: 10.1021/jm401753e. Epub 2014 Feb 5.
We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-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 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
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