Idasanutlin(RG-7388)
cas 1229705-06-9
4-{ [(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-prop yl)-pyrrolidine-2-carbonyl] -amino }-3-methoxy-benzoic acid (C31H29Cl2F2N304)
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid
MW 616.4973
J. Med. Chem., 2013, 56 (14), pp 5979–5983
DOI: 10.1021/jm400487c
http://pubs.acs.org/doi/suppl/10.1021/jm400487c/suppl_file/jm400487c_si_001.pdf synthesis as compd 12
Restoration of p53 activity by inhibition of the p53–MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein–protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53–MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.
compd 12
1H NMR (400 MHz, DMSO-d6)
δ12.86 (s, 1 H), 10.46 (s, 1 H), 8.35 (d, J = 8.86 Hz, 1 H), 7.71 (t, J = 6.95 Hz, 1 H), 7.48 – 7.61 (m,4 H), 7.29 – 7.42 (m, 3 H), 4.53 – 4.61 (m, 2 H), 4.38 (br. s., 1 H), 3.86 – 3.99 (m, 4 H), 1.62 (dd,J = 9.87, 14.00 Hz, 1 H), 1.24 (d, J = 14.00 Hz, 1 H), 0.95 (s, 9 H) ppm;
13C NMR (101 MHz, DMSO-d6) δ 171.2, 166.9, 160.8, 158.3, 156.8, 154.4, 147.5, 134.8, 134.7, 131.0, 130.8, 130.0,
128.6, 126.1, 125.9, 125.6, 125.3, 122.7, 119.6, 119.4, 119.2, 119.1, 117.7, 117.4, 117.3, 117.2, 111.0,
64.7, 63.4, 63.3, 63.3, 63.2, 55.8, 50.2, 43.9, 30.1, 29.5, 25.5 ppm;
128.6, 126.1, 125.9, 125.6, 125.3, 122.7, 119.6, 119.4, 119.2, 119.1, 117.7, 117.4, 117.3, 117.2, 111.0,
64.7, 63.4, 63.3, 63.3, 63.2, 55.8, 50.2, 43.9, 30.1, 29.5, 25.5 ppm;
HRMS (ES+) m/z CalcdC31H29Cl2F2N3O3+ H [M+H]+: 616.1576, found: 616.1574.
Anal. Calcd for C31H29Cl2F2N3O3: C, 60.4; H, 4.74; Cl, 11.5; F, 6.16; N, 6.82. Found: C, 60.3; H, 4.79; Cl, 11.3; F, 6.02; N, 6.82.