Table 1. Inhibitory Potencies and Structures of Hit Compound 1 and All of the Synthesized Inhibitors and Positive Controlsa.
| structure |
IC50 ± SEM [nM] or % RA ± SD at 100 μM |
|||||
|---|---|---|---|---|---|---|
| compd | Pdpb | linker | R | hMAO-A | hMAO-B | selectivity ratioc |
| 1 | 1,4 | trans-vinyl | 4-F | 60.2 ± 1.6% | 342.2 ± 22.4 | >292 |
| 6 | 1,4 | cis-vinyl | 4-F | 726.1 ± 26.9 | 6221.5 ± 726.8 | 0.12 |
| 25 | 1,4 | ethyl | 4-F | 76.9 ± 2.2% | 370.1 ± 37.3 | >270 |
| 21 | 1,4 | cis-vinyl | 2,4,5-F | 5243.7 ± 323.4 | 66.5 ± 3.9% | <0.05 |
| 22 | 1,4 | trans-vinyl | 2,4,5-F | 81.2 ± 3.1% | 436.2 ± 11.7 | >229 |
| 26 | 1,4 | ethyl | 2,4,5-F | 65.6 ± 4.4% | 216.4 ± 14.2 | >462 |
| 19 | 1,3 | trans-vinyl | 4-F | 91.0 ± 3.1% | 1469.5 ± 233.2 | >68 |
| 23 | 1,3 | ethyl | 4-F | 93.1 ± 3.2% | 7411.6 ± 1190.0 | >13 |
| 20 | 1,3 | trans-vinyl | 2,4,5-F | 102.5 ± 5.2% | 2195.6 ± 228.3 | >46 |
| 24 | 1,3 | ethyl | 2,4,5-F | 86.0 ± 5.2% | 11229.4 ± 974.7 | >9 |
| 67 | 1,4 | cis-vinyl | H | 168.8 ± 8.5 | 79.1 ± 4.0% | <0.002 |
| 68 | 1,4 | trans-vinyl | H | 32960.7 ± 3476.5 | 3540.2 ± 611.8 | 9 |
| 93 | 1,4 | ethyl | H | 75779.6 ± 7566.0d | 4603.4 ± 371.1 | 16 |
| 69 | 1,4 | cis-vinyl | 3-F | 68.4 ± 4.3 | 48912.0 ± 2525.4 | 0.001 |
| 70 | 1,4 | trans-vinyl | 3-F | 6906.8 ± 860.2 | 5048.7 ± 1224.6 | 1.4 |
| 94 | 1,4 | ethyl | 3-F | 19927.3 ± 1608.5 | 3363.5 ± 310.5 | 6 |
| 71 | 1,4 | cis-vinyl | 2-F | 3013.7 ± 207.3 | 65.5 ± 0.3% | <0.03 |
| 72 | 1,4 | trans-vinyl | 2-F | 27293.2 ± 1758.4 | 11830.4 ± 766.5 | 2 |
| 95 | 1,4 | ethyl | 2-F | 5927.3 ± 223.8 | 14159.5 ± 708.9 | 0.4 |
| 73 | 1,4 | cis-vinyl | 2-Cl-4-F | 46121.5 ± 10141.6 | 53000.5 ± 2662.5 | 0.9 |
| 74 | 1,4 | trans-vinyl | 2-Cl-4-F | 66028.4 ± 8419.0 | 417.6 ± 46.9 | 158 |
| 75 | 1,4 | cis-vinyl | 4-Me | 62.2 ± 4.4% | 19162.8 ± 5139.7 | >5 |
| 76 | 1,4 | trans-vinyl | 4-Me | 57.3 ± 2.9% | 147.0 ± 13.8 | >680 |
| 96 | 1,4 | ethyl | 4-Me | 68.1 ± 1.6% | 159.0 ± 13.3 | >630 |
| 77 | 1,4 | cis-vinyl | 4-iPr | 83.2 ± 0.5% | 1883.9 ± 278.6 | >53 |
| 78 | 1,4 | trans-vinyl | 4-iPr | 73638.2 ± 11010.1d | 44.4 ± 8.2 | 1658 |
| 97 | 1,4 | ethyl | 4-iPr | 162399.3 ± 9715.9d | 7.0 ± 2.2 | 23200 |
| 79 | 1,4 | cis-vinyl | 4-Cl | 118844.3 ± 26412.7d | 11745.1 ± 555.9 | 10 |
| 80 | 1,4 | trans-vinyl | 4-Cl | 71.7 ± 0.2% | 50.4 ± 4.7 | >1984 |
| 98 | 1,4 | ethyl | 4-Cl | 67.7 ± 0.0% | 38.1 ± 6.8 | >2625 |
| 81 | 1,4 | trans-vinyl | 4-Br | 54.5 ± 1.2% | 21.2 ± 4.2 | >4717 |
| 82 | 1,4 | trans-vinyl | 4-OMe | 56.1 ± 1.6% | 68.1 ± 11.1 | >1468 |
| 99 | 1,4 | ethyl | 4-OMe | 62.2 ± 1.9% | 67.0 ± 11.4 | >1493 |
| 83 | 1,4 | cis-vinyl | 4-CF3 | 80.1 ± 4.5% | 1506.6 ± 216.3 | >66 |
| 84 | 1,4 | trans-vinyl | 4-CF3 | 64.9 ± 0.5% | 18.6 ± 3.3 | >5376 |
| 100 | 1,4 | ethyl | 4-CF3 | 62.3 ± 0.7% | 10.9 ± 3.0 | >9174 |
| 85 | 1,4 | cis-vinyl | 3-CF3 | 858.0 ± 29.2 | 9352.5 ± 1512.9 | 0.09 |
| 86 | 1,4 | trans-vinyl | 3-CF3 | 64.8 ± 4.0% | 549.7 ± 127.5 | >182 |
| 101 | 1,4 | ethyl | 3-CF3 | 71.6 ± 2.2% | 501.8 ± 107.1 | >199 |
| 87 | 1,4 | cis-vinyl | 4-CN | 68.1 ± 2.7% | 1745.3 ± 315.4 | >57 |
| 88 | 1,4 | trans-vinyl | 4-CN | 129064.0 ± 8079.7d | 57.0 ± 7.1 | 2264 |
| 102 | 1,4 | ethyl | 4-CN | 21478.3 ± 6280.3 | 56.6 ± 8.7 | 379 |
| 89 | 1,4 | cis-vinyl | 4-SO2Me | 70.6 ± 5.8% | 8444.7 ± 627.1 | >12 |
| 90 | 1,4 | trans-vinyl | 4-SO2Me | 68.7 ± 0.2% | 32.7 ± 2.5 | >3058 |
| 91 | 1,4 | cis-vinyl | 4-cyclopropyl | 7398.7 ± 661.8 | 2640.1 ± 342.8 | 3 |
| 92 | 1,4 | trans-vinyl | 4-cyclopropyl | 20564.5 ± 2315.8 | 43.7 ± 6.4 | 471 |
| 103 | 1,4 | ethyl | 4-propyl | 80305.3 ± 9033.0 | 36.1 ± 4.1 | 2225 |
| 104 | 1,4 | cis-vinyl | 4-CONH2 | 89.5 ± 0.6% | 51019.0 ± 6046.5 | 2 |
| 105 | 1,4 | trans-vinyl | 4-CONH2 | 64.8 ± 1.1% | 1737.0 ± 691.0 | 58 |
| 106 | 1,4 | ethyl | 4-CONH2 | 75.1 ± 2.2% | 5554.5 ± 1778.9 | >18 |
| 107 | 1,4 | ethyl | 4-OH | 67.7 ± 0.5% | 7440.7 ± 1291.3 | >13 |
| pargyline | 3967.9 ± 275.1 | 195.5 ± 19.1 | 20 | |||
| l-deprenyl | 62663.8 ± 4113.6 | 12.1 ± 4.2 | 5179 | |||
| rasagiline | 29520 ± 8597 | 36.0 ± 4.1 | 820 | |||
| clorgiline | 3.4 ± 0.3 | 13568.4 ± 1157.3 | 0.0003 | |||
a
Data are mean values ± SEM: IC50 (in boldface), n = 2, 3; residual activity (RA), n = 2.
b
Pdn: piperidine disubstitution pattern.
c
Selectivity ratio is defined as IC50(hMAO-A)/IC50(hMAO-B).
d
Estimated IC50 values from the RAs below 100 μM. Compounds showed precipitation in the assay buffer at concentrations above 100 μM.