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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 6.

Amide substitution SAR.

graphic file with name nihms-1769820-t0046.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
70 Me H 1.5 ± 0.0 87 ± 3 64 ± 5
71 Me Me 1.2 ± 0.1 98 ± 3 2.0 ± 0.1 86 ± 1
72 iPr H 2.8 ± 0.2 47 ± 1 54 ± 2
73 tBu H 65 ± 5 49 ± 4
74 iBu H > 38 0.81 ± 0.05 56 ± 1
75 CH2CH2OH H 0.42 ± 0.00 104 ± 3 2.0 ± 0.1 96 ± 2
76 CH2CH2OMe H 2.1 ± 0.0 92 ± 2 0.73 ± 0.10 102 ± 5
77 CH2CO2H H 1.2 ± 0.0 106 ± 2 11 ± 1 87 ± 4
78 CH2CH2NH2 H 0.38 ± 0.00 97 ± 1 2.0 ± 0.1 89 ± 1
79 CH2CH2NHMe H 0.87 ± 0.06 101 ± 3 0.32 ± 0.02 96 ± 2
80 CH2CONH2 H 1.6 ± 0.1 105 ± 3 3.8 ± 0.0 77 ± 14
81 CH2CH2CH2NHMe H 1.0 ± 0.1 104 ± 3 0.91 ± 0.06 95 ± 0
82 Ph H 40 ± 21 69 ± 11
83 CH2Ph H > 38 41 ± 1
84 cyclohexyl H > 38 31 ± 7
85 N-piperidine 51 ± 0 65 ± 3
86 N-morpholine 4.2 ± 0.0 82 ± 4 4.1 ± 0.3 71 ± 2
87 N-piperazine 0.21 ± 0.00 103 ± 3 1.5 ± 0.0 93 ± 2
88 N-4-Me-piperazine 2.9 ± 0.2 88 ± 1 1.2 ± 0.1 86 ± 3
a

IC50 values were determined utilizing the diaphorase and resazurin-coupled mIDH1 R132H and R132C assays. IC50 is reported for compounds with >75% inhibition at 38μM, the highest concentration tested.