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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 10.

SAR at the pyridinone N1-aryl ring.

graphic file with name nihms-1769820-t0052.jpg
Biochemical IDH1 R132H IDH1 R132C
Compd R9 R10 R11 IC50(μM) ± SDa IC50(μM)± SDa
92 Et H Et 0.044 ± 0.003 0.058 ± 0.010
113 H H H 0.33 ± 0.00 3.2 ± 0.6
114 Et H H 0.056 ± 0.004 0.16 ± 0.01
115 Et H Me 0.27 ± 0.00 2.2 ± 0.2
116 Et H Cl 0.044 ± 0.003 0.055 ± 0.004
117 Et Me H 0.044 ± 0.003 0.11 ± 0.02
118 0.114 ± 0.007 0.075 ± 0.000
(+)−118 0.12 ± 0.02 0.13 ± 0.03
(−)−118 Et OMe H 0.42 ± 0.05 0.67 ± 0.04
119 0.114 ± 0.007 0.10 ± 0.01
(+)−119 0.081± 0.005 0.072 ± 0.005 NCATS-SM5637, NSC 791985
(−)−119 Et Cl H 0.25 ± 0.04 0.54 ± 0.10
AG-120 0.065 ± 0.009 0.063 ± 0.015
a

IC50 values were determined utilizing the diaphorase and resazurin-coupled R132H and R132C mIDH1 assays. All compounds showed >80% inhibition at 38 μM, the highest concentration tested.