Table 3.
SAR Evaluation of Sulfonamide Aromatic Ring
 | ||||
|---|---|---|---|---|
| Cmpd | R | hEC50 (µM) | % PHCCC | Yieldc (%) |
| 25a | phenyl | 3.5 ± 0.7 | 69.7 ± 5.1 | 80 |
| 25b | 2-fluorophenyl | 3.5 ± 0.5 | 36.6 ± 1.8 | 3d |
| 25c | 2-chlorophenyl | >10 | 25.8 ± 2.5 | 58 |
| 25d | 2-methoxyphenyl | Inactiveb | 21.8 ± 1.0 | 87 |
| 25e | 2-(trifluoromethyl)phenyl | Inactiveb | 20.1 ± 0.2 | 24d |
| 25f | 3-(trifluoromethyl)phenyl | Inactiveb | 18.2 ± 1.9 | 6d |
| 25g | 4-(trifluoromethyl)phenyl | 2.5 ± 0.5 | 26.6 ± 2.3 | 36 |
| 25h | 4-(trifluoromethoxy)phenyl | >10 | 48.2 ± 4.6 | 5d |
| 25i | 4-methylphenyl | 3.3 ± 0.2 | 48.7 ± 1.1 | 77 |
| 25j | 4-fluorophenyl | >10 | 27.6 ± 1.3 | 33d |
| 25k | 4-chlorophenyl | 4.1 ± 0.6 | 43.6 ± 4.4 | 41 |
| 25l | 4-tertbutylphenyl | >10 | 32.6 ± 3.1 | 32 |
| 25m | 4-acetylphenyl | >10 | 42.9 ± 2.7 | 65 |
| 25n | 2,4-dimethylphenyl | 1.3 ± 0.5 | 42.8 ± 4.1 | 58 |
| 25o | 2,5-dimethylphenyl | 2.7 ± 0.6 | 32.5 ± 1.2 | 67 |
| 25p | 2,5-dichlorophenyl | Inactiveb | 22.7 ± 0.7 | 67 |
| 25q | 2-chloro-6-methylphenyl | Inactiveb | 18.1 ± 0.9 | 75 |
| 25r | 2,6-dichlorophenyl | Inactiveb | 22.3 ± 1.7 | 23 |
| 25s | 3,4-dimethylphenyl | 3.2 ± 0.2 | 42.4 ± 5.0 | 67 |
| 25t | 3-chloro-4-methylphenyl | 3.4 ± 0.2 | 39.2 ± 1.2 | 43 |
| 25u | 3,4-dichlorophenyl | >10 | 24.3 ± 1.5 | 31 |
| 25v | 3,4-difluorophenyl | >10 | 27.0 ± 1.8 | 64 |
| 25w | 4-chloro-3-fluorophenyl | 4.5 ± 0.7 | 25.5 ± 1.2 | 53 |
| 25x | 2,4-dichloro-5-methylphenyl | 3.1 ± 0.9 | 43.6 ± 4.7 | 44 |
| 25y | 4-chloro-2-fluoro-5-methylphenyl | 2.7 ± 0.2 | 36.9 ± 2.7 | 36 |
| 25z | benzyl | >10 | 46.5 ± 4.8 | 12d |
| 25aa | 2,4-dichlorobenzyl | 2.8 ± 0.01 | 34.4 ± 3.5 | 44 |
| 25ab | isopropyl | Inctiveb | 17.5 ± 0.7 | 22d |
| 25ac | isobutyl | Inactiveb | 21.3 ± 0.9 | 27d |
| 25ad | 2-pyridyl | Inactiveb | 20.6 ± 0.3 | 36 |
| 25ae | 2-thiophene | 1.8 ± 0.3 | 52.9 ± 5.0 | 83 |
| 25af | 2-furyl | 3.3 ± 0.3 | 36.2 ± 2.2 | 98 |
| 25ag | 3-pyridyl | >10 | 25.6 ± 4.6 | 20 |
| 25ah | 3-furyl | >10 | 34.1 ± 3.6 | 70 |
| 25ai | 3-thiophene | >10 | 35.0 ± 3.3 | 79 |
| 25aj | 2-acetamidothiazol-5-yl | >10 | 46.4 ± 5.5 | 60 |
| 25ak | 2,4-dimethylthiazol-5-yl | >10 | 47.7 ± 2.1 | 73 |
| 25al | 2-methyl-5-(trifluoromethyl)thiazol-5-yl (±)-PHCCC |
2.5 ± 0.4 3.1 ± 0.3 |
28.1 ± 4.8 | 49 |
a
EC50 and GluMax, are the average of at least three independent determinations performed in triplicate (Mean ± SEM shown in table). PHCCC is run as a control compound each day, and the maximal response generated in mGlu4 CHO cells in the presence of mGlu4 PAMs varies slightly in each experiment. Therefore, data were further normalized to the relative PHCCC response obtained in each day’s run.
b
Inactive compounds are defined as %GluMax did not surpass 2X the EC20 value for that day’s run.
c
All yields were obtained by reverse phase preparative HPLC unless otherwise stated and were optimized for purity (>95%) not yield.
d
Yields obtained by mass directed HPLC17