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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 3.

Pyridone Aryl Substituent SAR

graphic file with name nihms-1769820-t0041.jpg
Biochemical IDH1 R132H IDH1 R132C
Compd R1 IC50(μM) ± SDa % inhibition ± SD at 38 μM IC50(μM) ± SDa % inhibition ± SD at 38 μM
1 2,5-(OMe)2Ph 1.6 ± 0.2 84 ± 7 1.0 ± 0.3 85 ± 9
27 Ph - 47 ± 3 - 38 ± 2
28 2-OMe-Ph 2.4 ± 0.5 76 ± 3 - 65 ± 2
29 2-OEt-Ph 0.51 ± 0.03 88 ± 6 0.41 ± 0.03 81 ± 3
30 2-OiPr-Ph 1.1 ± 0.2 80 ± 2 0.47 ± 0.05 77 ± 1
31 2-Me-Ph - 74 ± 4 - 64 ± 2
32 2-Et-Ph 2.0 ± 0.1 91 ± 1 0.87 ± 0.28 83 ± 7
33 2-iPr-Ph - 62 ± 3 - 61 ± 6
34 2-Ph-Ph - 59 ± 2 - 67 ± 2
35 2-OH-Ph - 71 ± 1 - 61 ± 3
36 2-OPh-Ph - 30 ± 1 - 60 ± 2
37 2-OBn-Ph - 38 ± 2 - 61 ± 2
38 2-NH2-Ph - 57 ± 0 - 42 ± 2
39 2-NHMe-Ph - 59 ± 3 - 43 ± 1
40 2-NMe2-Ph - 56 ± 4 - 57 ± 7
41 2-CO2H-Ph 4.6 ± 0.3 96 ± 5 11 ± 1 105 ± 7
42 2-F-Ph - 65 ± 5 - 49 ± 3
43 2-Cl-Ph 1.3 ± 0.1 83 ± 1 - 70 ± 1
44 2-CF3-Ph 0.27 ± 0.00 96 ± 2 0.20 ± 0.01 87 ± 2
45 2-OCF3-Ph 0.57 ± 0.04 98 ± 2 0.28 ± 0.02 78 ± 13
46 2-Py - 47 ± 2 - 39 ± 1
47 2-OMeBn - 61 ± 12 - 53 ± 1
48 α-MeBn > 38 - - 34 ± 1
49 iPr - 31 ± 8 - 33 ± 1
50 cyclohexyl > 38 - > 38 -
51 graphic file with name nihms-1769820-t0042.jpg 0.47 ± 0.01 94 ± 1 0.47 ± 0.01 83 ± 4
52 graphic file with name nihms-1769820-t0043.jpg 0.26 ± 0.02 100 ± 1 0.25 ± 0.02 90 ± 2
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).