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. Author manuscript; available in PMC: 2022 Mar 31.
Published in final edited form as: J Med Chem. 2021 Apr 6;64(8):4913–4946. doi: 10.1021/acs.jmedchem.1c00019

Table 4.

Pyridone Aryl Substituent SAR continued.

graphic file with name nihms-1769820-t0044.jpg
Biochemical IDH1 R132H IDH1 R132C
Compd R4 R5 IC50(μM) ± SDa % inhibition ± SD at 38 μM IC50(μM) ± SDa % inhibition ± SD at 38 μM
1 OMe 5-OMe 1.6 ± 0.2 84 ± 7 1.0 ± 0.3 85 ± 9
53 OMe 3-OMe - 64 ± 17 - 35 ± 3
54 OMe 4-OMe > 38 - > 38 -
55 OMe 6-OMe 2.4 ± 0.1 87 ± 2 1.6 ± 0.2 75 ± 7
56 OMe 3-CO2H 14 ± 1 82 ± 2 - 65 ± 2
57 OMe 4-CO2H > 38 - - 43 ± 6
58 OMe 5-CO2H 12 ± 1 108 ± 2 14 ± 1 86 ± 4
59 OMe 6-CO2H 0.91 ± 0.06 102 ± 3 2.0 ± 0.1 108 ± 1
60 OMe 6-Me 2.1 ± 0.1 81 ± 2 - 72 ± 1
61 OMe 3-N (Py) 1.0 ± 0.1 97 ± 1 1.3 ± 0.2 80 ± 1
62 OMe 5-N (Py) > 38 - > 38 -
63 OEt 5-OEt 0.16 ± 0.01 85 ± 1 0.064 ± 0.004 75 ± 1
64 OEt 6-OEt 0.39 ± 0.03 76 ± 4 0.16 ± 0.02 86 ± 7
65 Et 6-Me 0.79 ± 0.18 89 ± 1 0.50 ± 0.09 86 ± 3
66 Et 6-Et 0.69 ± 0.05 89 ± 2 0.24 ± 0.05 82 ± 4
a

IC50 values were determined utilizing the diaphorase and resazurin-coupled R132H and R132C mIDH1 assays (average of N = 3). IC50 values are reported only for compounds where ≥75% inhibition of enzyme activity was observed at the highest concentration tested (38 μM).