ChemicalBook Product Catalog Biochemical Engineering Biochemical Reagents Agonist Inhibitors [(4R,5S)-4,5-Bis(4-chlorophenyl)-2-[4-(1,1-dimethylethyl)-2-ethoxyphenyl]-4,5-dihydro-4,5-dimethyl-1H-imidazol-1-yl][4-[3-(methylsulfonyl)propyl]-1-piperazinyl]methanone

[(4R,5S)-4,5-Bis(4-chlorophenyl)-2-[4-(1,1-dimethylethyl)-2-ethoxyphenyl]-4,5-dihydro-4,5-dimethyl-1H-imidazol-1-yl][4-[3-(methylsulfonyl)propyl]-1-piperazinyl]methanone

Product Name[(4R,5S)-4,5-Bis(4-chlorophenyl)-2-[4-(1,1-dimethylethyl)-2-ethoxyphenyl]-4,5-dihydro-4,5-dimethyl-1H-imidazol-1-yl][4-[3-(methylsulfonyl)propyl]-1-piperazinyl]methanone
CAS939981-39-2
MFC38H48Cl2N4O4S
MW727.79
EINECS
MOL File939981-39-2.mol

Chemical Properties

Boiling point	790.399±70.00 °C(Press: 760.00 Torr)(predicted)
Density	1.23
storage temp.	Store at -20°C
solubility	≥36.4 mg/mL in DMSO; insoluble in H2O; ≥31.87 mg/mL in EtOH
form	solid
pka	6.569±0.10(predicted)
color	White to off-white
InChIKey	QBGKPEROWUKSBK-QPPIDDCLSA-N
SMILES	C(N1C(C2=CC=C(C(C)(C)C)C=C2OCC)=N[C@](C2=CC=C(Cl)C=C2)(C)[C@]1(C1=CC=C(Cl)C=C1)C)(N1CCN(CCCS(C)(=O)=O)CC1)=O

Safety Information

WGK Germany	WGK 3
Storage Class	11 - Combustible Solids
Hazard Classifications	Acute Tox. 4 Oral

Usage And Synthesis

Description

RG-7112 is an inhibitor of mouse double-minute 2 protein (MDM2; IC₅₀ = 0.018 μM), an E3 ubiquitin ligase that ubiquitinates the tumor suppressor p53 and also acts as a negative regulator of p53 transcriptional activity. RG-7112 binds to the p53 binding pocket of MDM2. It increases the levels of p53 and its transcriptional targets in SJSA-1 osteosarcoma cells. It inhibits proliferation in cancer cell lines expressing wild-type p53 (IC₅₀s = 0.18-2.2 μM) and cell lines expressing mutant p53 (IC₅₀s = 5.7-20.3 μM). RG-7112 also prevents and reduces tumor growth in an SJSA-1 mouse xenograft model when administered at doses of 50 and 100 mg/kg per day, respectively. However, it inhibits thrombopoiesis in vivo, decreasing platelet counts in rats when administered at doses of 50 and 100 mg/kg and in cynomolgus monkeys at doses of 10 and 20 mg/kg.

Uses

RG 7112 is MDM2 antagonist. It can be used in biological study of single mouse analysis on evaluation of alternative in vivo drug screening methodology.

in vivo

RG7112 (25-200 mg/kg, single oral dose) activates p53 pathway and induces apoptosis in tumor cells in vivo^[2].
RG7112 (100 mg/kg, gavage once per day, 5 days/week for 3 weeks ) reduces tumor growth rate and increases survival in GBM models^[3].

Animal Model:	Female Balb/c nude mice^[2].
Dosage:	25-200 mg/kg.
Administration:	Orally, single dose.
Result:	At the highest dose level of RG7112 (200 mg/kg) only 1.2% (± 0.89 SD) of cells incorporated BrdU at 24 h post-dosing, vs. 14% (± 1.83 SD) of vehicle treated tumors.

Animal Model:	GBM cells were implanted into the brain of Athymic Nude mice (7 weeks old females, 10 animals/group)^[3].
Dosage:	100 mg/kg.
Administration:	Oral gavage, once per day, 5 days/week for 3 weeks.
Result:	Reduced tumor growth rate and increases survival in heterotopic and orthotopic animal models bearing MDM2-amplified GBM.

target

MDM2

References

[1] BINH VU*. Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development[J]. ACS Medicinal Chemistry Letters, 2013, 4 5: 466-469. DOI: 10.1021/ml4000657
[2] CHRISTIAN TOVAR. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models.[J]. Cancer research, 2013, 73 8: 2587-2597. DOI: 10.1158/0008-5472.can-12-2807
[3] CAMELIA IANCU-RUBIN . Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis[J]. Experimental hematology, 2014, 42 2: Pages 137-145.e5. DOI: 10.1016/j.exphem.2013.11.012

Preparation Products And Raw materials

[(4R,5S)-4,5-Bis(4-chlorophenyl)-2-[4-(1,1-dimethylethyl)-2-ethoxyphenyl]-4,5-dihydro-4,5-dimethyl-1H-imidazol-1-yl][4-[3-(methylsulfonyl)propyl]-1-piperazinyl]methanone Supplier

[(4R,5S)-4,5-Bis(4-chlorophenyl)-2-[4-(1,1-dimethylethyl)-2-ethoxyphenyl]-4,5-dihydro-4,5-dimethyl-1H-imidazol-1-yl][4-[3-(methylsulfonyl)propyl]-1-piperazinyl]methanone manufacturers

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