Table 1. Structure-Activity Relationships for mGlu5 Negative Allosteric Modulators from Four Diverse Scaffolds Chosen for This Studya.
| allosteric ligand | ID | Confb | IC50 (nM) | ref |
|---|---|---|---|---|
| acetylene NAM (MPEP) series | ||||
| 3-((6-methylpyridin-2-yl)ethynyl)benzonitrile | 1A | 76 | 0.4 | (27) |
| 2-methyl-4-((6-phenylpyridin-3-yl)ethynyl)thiazole | 1B | 13 | 0.5 | (47) |
| 2-((3-methoxyphenyl)ethynyl)-6-methylpyridine | 1C | 571 | 8 | (28) |
| 2-methyl-6-((5-phenylpyridin-3-yl)ethynyl)pyridine | 1D | 21 | 20 | (48) |
| 2-methyl-6-(phenylethynyl)pyridine | 1E | 735 | 9 | (25) |
| 2-((2,5-dimethoxyphenyl)ethynyl)-6-methylpyridine | 1F | 7 | 82 | (28) |
| 2-((3-methoxyphenyl)ethynyl)-5-methylpyridine | 1G | 459 | 114 | (13) |
| 2-methoxy-6-(phenylethynyl)pyridine | 1H | 651 | 1961 | (28) |
| methyl 2-(3-((6-methylpyridin-2-yl)ethynyl)phenoxy)acetate | 1I | 553 | 2400 | (48) |
| 3-((6-methylpyridin-2-yl)ethynyl)phenyl 4-methylbenzenesulfonate | 1J | 82 | >10 000 | (48) |
| N-aryl benzamide NAM (VU0366248) series | ||||
| 2-cyano-4′-fluoro-N-(6-methylpyridin-2-yl)-[1,1′-biphenyl]-4-carboxamide | 2A | 11 | 5 | (29) |
| 2-cyano-N-(6-methylpyridin-2-yl)-[1,1′-biphenyl]-4-carboxamide | 2B | 10 | 14 | (29) |
| N-(3-chlorophenyl)-3-cyano-5-fluorobenzamide | 2C | 8 | 45 | (42) |
| 3-cyano-N-(6-ethylpyridin-2-yl)-5-fluorobenzamide | 2D | 26 | 59 | (29) |
| N-(3-chloro-2-fluorophenyl)-3-cyano-5-fluorobenzamide | 2E | 8 | 347 | (42) |
| N-(3-chloro-4-fluorophenyl)-3-cyano-5-fluorobenzamide | 2F | 8 | 377 | (42) |
| 3-cyano-N-(6-methylpyridin-2-yl)benzamide | 2G | 10 | 490 | (29) |
| 3-cyano-5-fluoro-N-phenylbenzamide | 2H | 4 | 5440 | (42) |
| N-(adamantan-1-yl)-3-cyano-5-fluorobenzamide | 2I | 12 | >10 000 | (42) |
| 4-aryl-5-cyanopyrimidine (VU0366058) series | ||||
| 2-(benzo[d]oxazol-2-ylamino)-4-(2-methoxyphenyl)pyrimidine-5-carbonitrile | 3A | 8 | 62 | (26) |
| 2-(benzo[d]oxazol-2-ylamino)-4-phenylpyrimidine-5-carbonitrile | 3B | 8 | 89 | (26) |
| 2-(benzo[d]oxazol-2-ylamino)-4-(4-fluorophenyl)pyrimidine-5-carbonitrile | 3C | 8 | 91 | (26) |
| 2-(benzo[d]oxazol-2-ylamino)-4-cyclohexylpyrimidine-5-carbonitrile | 3D | 22 | 216 | (26) |
| 2-(benzo[d]oxazol-2-ylamino)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile | 3E | 16 | 223 | (26) |
| 2-(benzo[d]oxazol-2-ylamino)-4-(3,5-dimethoxyphenyl)pyrimidine-5-carbonitrile | 3F | 32 | >10 000 | (26) |
| 2-(benzo[d]oxazol-2-ylamino)-4-(pyridin-2-yl)pyrimidine-5-carbonitrile | 3G | 8 | >10 000 | (26) |
| 2-(benzo[d]oxazol-2-ylamino)-4-(naphthalen-2-yl)pyrimidine-5-carbonitrile | 3H | 16 | >10 000 | (26) |
| Aryl ether benzamide NAM (VU0409106) series | ||||
| 3-chloro-5-((5-fluoropyridin-3-yl)oxy)-N-(6-methylpyridin-2-yl)benzamide | 5A | 84 | 5 | (30) |
| 3-chloro-N-(4-methylthiazol-2-yl)-5-(pyrimidin-5-yloxy)benzamide | 5B | 42 | 11 | (30) |
| 3-chloro-5-((5-cyanopyridin-3-yl)oxy)-N-(6-methylpyridin-2-yl)benzamide | 5C | 87 | 12 | (30) |
| 3-fluoro-N-(4-methylthiazol-2-yl)-5-(pyrimidin-5-yloxy)benzamide | 5D | 40 | 26 | (30) |
| 3-chloro-N-(6-methylpyridin-2-yl)-5-(pyrimidin-5-yloxy)benzamide | 5E | 42 | 26 | (30) |
| 3-chloro-N-(6-methoxypyridin-2-yl)-5-(pyrimidin-5-yloxy)benzamide | 5F | 82 | 49 | (30) |
| N-(5-fluoropyridin-2-yl)-3-methoxy-5-(pyrimidin-5-yloxy)benzamide | 5G | 89 | 85 | (30) |
| N-(4-methylthiazol-2-yl)-3-(pyrimidin-5-yloxy)benzamide | 5H | 32 | 205 | (30) |
| N-(pyridin-2-yl)-3-(pyridin-3-yloxy)benzamide | 5I | 84 | 844 | (30) |
| 3-chloro-5-(pyrimidin-5-yloxy)-N-(5-(trifluoromethyl)pyridin-2-yl)benzamide | 5J | 38 | >10 000 | (30) |
| 3-chloro-N-(3-fluoropyridin-2-yl)-5-(pyrimidin-5-yloxy)benzamide | 5K | 45 | >10 000 | (30) |
| N-(5-bromo-4-methylthiazol-2-yl)-3-fluoro-5-((2-methylpyrimidin-5-yl)oxy)benzamide | 5L | 83 | >10 000 | (30) |
a
Structures for each compound are found in the Supporting Information.
b
Number of conformers computed for each ligand for docking.