RG-7388

Idasanutlin (RG7388) is a potent and selective MDM2 antagonist, inhibiting p53-MDM2 binding, with an IC50 of 6 nM.

Idasanutlin has been used in trials studying the treatment of Neoplasms, Non-Hodgkin's Lymphoma, Leukemia, Myeloid, Acute, Recurrent Plasma Cell Myeloma, and Neoplasms, Leukemia, Acute Myeloid Leukemia.|Idasanutlin is an orally available, small molecule, antagonist of MDM2 (mouse double minute 2; Mdm2 p53 binding protein homolog), with potential antineoplastic activity. Idasanutlin binds to MDM2 blocking the interaction between the MDM2 protein and the transcriptional activation domain of the tumor suppressor protein p53. By preventing the MDM2-p53 interaction, p53 is not enzymatically degraded and the transcriptional activity of p53 is restored. This may lead to p53-mediated induction of tumor cell apoptosis. MDM2, a zinc finger nuclear phosphoprotein and negative regulator of the p53 pathway, is often overexpressed in cancer cells and has been implicated in cancer cell proliferation and survival.

To a solution of compound 10a (20 mg, 0.03 mmol) in MeCN(2 mL), compound 11 (20 mg, 0.03 mmol), HATU (15 mg, 0.04 mmol) and DIPEA (7 mL, 0.04 mmol) were added. The mixturewas stirred at room temperature for 30 min. After completion of thereaction monitored by TLC, The solvent was evaporated in vacuo, and the residue was purified by column chromatography (elutedwith trichloromethane/methanol 20c/1) to give compound 14i(32 mg, 87% yield). HRMS (ESI) for C65H68N11O7F2Cl2 [MH], Calcd: 1222.4648, Found: 1222.4617. HPLC analysis: MeOH-H2O(95:5), RT 5.460 min, 99.17% purity. 1H NMR (400 MHz, DMSO-d6)d 10.40 (s, 1H), 10.36 (s, 1H), 8.80 (s, 1H), 8.42 (d, J 5.5 Hz, 1H), 8.31(d, J 8.3 Hz, 1H), 8.13 (s, 1H), 7.95e7.84 (m, 1H), 7.73 (t, J 7.3 Hz, 1H), 7.61e7.46 (m, 6H), 7.36 (q, J 10.0, 9.2 Hz, 3H), 7.27 (d, J 8.5 Hz, 1H), 6.97 (d, J 7.8 Hz, 1H), 6.55 (s, 1H), 6.43 (dd, J 16.9, 10.2 Hz, 1H), 6.34e6.22 (m, 2H), 6.02 (s, 1H), 5.75 (d, J 10.0 Hz, 1H), 4.67e4.55 (m, 2H), 4.37 (t, J 10.0 Hz, 1H), 4.04e3.87 (m, 4H), 3.77 (s, 3H), 3.57 (s, 4H), 3.30e3.24 (m, 4H), 2.99 (d, J 21.4 Hz, 4H), 2.45 (s, 3H), 2.36 (t, J 7.4 Hz, 2H), 1.68e1.50 (m, 5H), 1.40e1.31 (m, 2H), 0.97 (s, 9H). 13C NMR (101 MHz, DMSO) d 171.50, 171.09, 165.82, 163.71, 162.61, 161.22, 158.72, 157.03, 156.72, 154.81, 147.98, 147.39, 140.38, 137.51, 135.18, 132.18, 131.44, 130.49, 130.36, 129.96, 129.64, 129.07, 127.63, 126.57, 126.42, 126.10, 125.77, 124.51, 120.84, 120.39, 120.16, 119.85, 119.67, 119.24, 118.18, 117.90, 117.78, 117.48, 117.05, 110.03, 107.26, 106.66, 100.80, 65.10, 63.95, 63.69, 56.25, 56.18, 50.61, 49.96, 49.54, 45.26, 44.36, 41.29, 32.66, 30.54, 29.95, 29.55, 26.75, 25.06, 17.47.General procedure: To a solution of compound 10a (20 mg, 0.03 mmol) in MeCN(2 mL), compound 11 (20 mg, 0.03 mmol), HATU (15 mg, 0.04 mmol) and DIPEA (7 mL, 0.04 mmol) were added. The mixturewas stirred at room temperature for 30 min. After completion of thereaction monitored by TLC, The solvent was evaporated in vacuo, and the residue was purified by column chromatography (elutedwith trichloromethane/methanol 20c/1) to give compound 14i(32 mg, 87% yield).General procedure: To a solution of compound 10a (20 mg, 0.03 mmol) in MeCN(2 mL), compound 11 (20 mg, 0.03 mmol), HATU (15 mg, 0.04 mmol) and DIPEA (7 mL, 0.04 mmol) were added. The mixturewas stirred at room temperature for 30 min. After completion of thereaction monitored by TLC, The solvent was evaporated in vacuo, and the residue was purified by column chromatography (elutedwith trichloromethane/methanol 20c/1) to give compound 14i(32 mg, 87% yield).General procedure: To a solution of compound 10a (20 mg, 0.03 mmol) in MeCN(2 mL), compound 11 (20 mg, 0.03 mmol), HATU (15 mg, 0.04 mmol) and DIPEA (7 mL, 0.04 mmol) were added. The mixturewas stirred at room temperature for 30 min. After completion of thereaction monitored by TLC, The solvent was evaporated in vacuo, and the residue was purified by column chromatography (elutedwith trichloromethane/methanol 20c/1) to give compound 14i(32 mg, 87% yield).A solution of compound 13 (72 mg, 0.10 mmol) in DCM (5 mL)and TFA (1 mL) was stirred at room temperature for 1 h and thesolvents were removed under reduced pressure. The resultingresidue was dissolved in MeCN (5 mL), then compound 11 (62 mg, 0.10 mmol), HATU (57 mg, 0.15 mmol) and DIPEA (0.09 mL, 0.50 mmol) were added to the solution. After completion of thereaction monitored by TLC, The solvent was evaporated in vacuo, and the residue was purified by column chromatography (elutedwith trichloromethane/methanol 20/1) to give compound 14d(65 mg, 50% yield over two steps). HRMS (ESI) for C71H82N11O6F2Cl2[MH], Calcd: 1292.5795, Found: 1292.5778. HPLC analysis:MeOH-H2O (95:5), RT 11.372 min, 98.94% purity. 1H NMR(400 MHz, DMSO-d6) d 10.38 (d, J 17.8 Hz, 2H), 8.79 (s, 1H), 8.44e8.26 (m, 2H), 8.09 (s, 1H), 7.89 (s, 1H), 7.73 (s, 1H), 7.64e7.42(m, 6H), 7.40e7.21 (m, 4H), 6.97 (d, J 8.1 Hz, 1H), 6.57e6.39 (m, 2H), 6.37e6.19 (m, 2H), 5.99 (s, 1H), 5.75 (d, J 10.1 Hz, 1H), 4.59 (s, 2H), 4.37 (s, 1H), 4.01e3.87 (m, 4H), 3.77 (s, 3H), 3.25 (s, 2H), 3.00 (s, 4H), 2.45 (s, 7H), 2.28 (s, 2H), 1.70e1.59 (m, 1H), 1.54e1.40 (m, 4H), 1.31e1.20 (m, 16H), 0.97 (s, 9H). 13C NMR (101 MHz, DMSO) d 171.48, 165.76, 163.70, 162.60, 161.22, 158.73, 157.26, 157.01, 156.74, 154.81, 147.96, 147.37, 140.41, 137.52, 135.29, 135.17, 132.20, 131.45, 130.48, 130.38, 130.11, 129.95, 129.62, 129.07, 127.55, 126.57, 126.44, 126.11, 125.77, 124.49, 120.39, 120.14, 120.03, 119.84, 119.69, 119.60, 119.19, 118.18, 117.90, 117.78, 117.4c7, 116.98, 110.01, 106.59, 100.03, 65.11, 63.91, 63.73, 58.36, 56.25, 56.13, 53.22, 50.61, 49.23, 44.36, 30.55, 29.96, 29.63, 29.54, 29.48, 29.27, 27.46, 26.98, 26.78, 17.47.

Molecular Weight:616.5
XLogP3:4.3
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:8
Rotatable Bond Count:8
Exact Mass:615.1503181
Monoisotopic Mass:615.1503181
Topological Polar Surface Area:111
Heavy Atom Count:42
Complexity:1040
Defined Atom Stereocenter Count:4
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes