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. Author manuscript; available in PMC: 2016 Sep 24.
Published in final edited form as: J Med Chem. 2015 Sep 10;58(18):7485–7500. doi: 10.1021/acs.jmedchem.5b01005

Table 6.

mGlu3 NAM and mGlu5 SAR of 5-Chloropyridin-2-yl Ether Analogues 80–101

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no. R mGlu3 pIC50 (± SEM)a mGlu3 IC50 (nM)a % Glu Max (± SEM)a,b mGlu5 activityc mGlu5 pEC50 (± SEM)c mGlu5 EC50 (nM)c % Glu Max (± SEM)b,c
80 2-fluorophenyl 6.65 ± 0.04 226 1.74 ± 0.10 PAM 5.49 ± 0.06 3240 57.3 ± 4.6
81 3-fluorophenyl 6.69 ± 0.04 206 1.38 ± 0.47 PAM 5.22 ± 0.05 5970 63.5 ± 0.8
82 2-chlorophenyl 6.48 ± 0.08 328 1.87 ± 0.29 PAM 5.26 ± 0.03 5450 51.0 ± 3.9
83 3-chlorophenyl 6.25 ± 0.07 558 1.63 ± 0.20 PAM 5.54 ± 0.02 2870 65.8 ± 8.8
84 4-chlorophenyl 5.91 ± 0.25 1230 0.94 ± 1.46 PAM 5.48 ± 0.15 3310 51.2 ± 10.3
85 2-methylphenyl 6.24 ± 0.18 571 1.95 ± 0.70 PAM 5.64 ± 0.03 2280 80.7 ± 0.5
86 3-methylphenyl 6.41 ± 0.05 392 1.71 ± 0.44 PAM 5.44 ± 0.11 3600 69.9 ± 6.5
87 4-methylphenyl 6.39 ± 0.21 410 1.39 ± 0.25 PAMe <5.0 >10000 70.8 ± 3.1
88 2-methoxyphenyl 6.16 ± 0.15 690 1.29 ± 0.18 NAMe <5.0 >10000 58.5 ± 1.2
89 3-methoxyphenyl 6.50 ± 0.05 313 2.00 ± 0.32 PAM 5.29 ± 0.08 5070 78.0 ± 1.8
90 4-methoxyphenyl 6.36 ± 0.11 439 2.07 ± 0.68 PAM 5.36 ± 0.06 4330 59.4 ± 7.3
91 2-cyanophenyl 6.37 ± 0.05 429 1.64 ± 0.04 PAM 5.30 ± 0.10 4970 38.1 ± 5.0
92 3-cyanophenyl 6.08 ± 0.26 825 1.75 ± 0.41 PAMe <5.0 >10000 32.2 ± 3.7
93 4-cyanophenyl 6.27 ± 0.05 539 1.84 ± 0.19 PAM 5.48 ± 0.08 3320 23.1 ± 6.8
94 2,3-difluorophenyl 6.07 ± 0.23 852 0.33 ± 0.71 PAM 5.17 ± 0.29 6680 36.1 ± 8.4
95 2,4-difluorophenyl 6.55 ± 0.08 280 1.34 ± 0.25 PAM 5.59 ± 0.07 2580 70.8 ± 0.8
96 2,6-difluorophenyl 6.65 ± 0.04 225 2.06 ± 0.31 PAM 5.85 ± 0.09 1420 40.3 ± 5.6
97 3,5-difluorophenyl 6.38 ± 0.07 420 2.18 ± 0.19 PAMe <5.0 >10000 33.1 ± 2.3
98 2-cyano-5-fluorophenyl 6.28 ± 0.06 529 1.55 ± 0.31 <4.5 >30000
99 3-cyano-5-fluorophenyl 6.50 ± 0.07 315 1.92 ± 0.12 PAM 5.98d 1044d 28.0d
100 pyridin-2-yl 6.48 ± 0.07 328 1.07 ± 0.04 <4.5 >30000
101 pyridin-3-yl 6.22 ± 0.10 608 1.73 ± 0.53 <4.5 >30000
a

Calcium mobilization mGlu3 assay; values are average of n ≥ 3.

b

Amplitude of response in the presence of 30 μM test compound as a percentage of maximal response (100 μM glutamate); average of n ≥ 3.

c

Calcium mobilization mGlu5 assay; values are average of n ≥ 3.

d

Average of n = 2.

e

Weak activity; CRC does not plateau.

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