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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 5.

In Vitro DMPK Profiling of Select 5-Fluoropyridin-2-yl Ether Analogues

graphic file with name nihms-766653-f0013.jpg
no. R cLogPa LLEb mGlu3 IC50 (nM) fold vs mGlu5 rat plasma Fuc rat CLhep (mL/min/kg)d
55 2-fluorophenyl 3.06 3.73 162 >61 0.098 64.7
56 3-fluorophenyl 3.06 3.66 192 14 0.094 53.0
57 2-chlorophenyl 3.57 3.28 141 7.2 0.054 66.5
58 3-chlorophenyl 3.57 3.27 145 13 0.034 51.9
61 3-methylphenyl 3.23 3.44 216 17 0.051 58.4
66 2,3-difluorophenyl 3.16 3.57 184 11 0.092 63.6
67 2,5-difluorophenyl 3.16 3.75 123 >81 0.089 49.6
68 2,6-difluorophenyl 3.16 3.58 181 6.8 0.064 64.6
a

Calculated using Dotmatics Elemental (www.dotmatics.com/products/elemental/).

b

LLE (ligand-lipophilicity efficiency) = pIC50 – cLogP.

c

Fu = fraction unbound.

d

Predicted hepatic clearance based on intrinsic clearance in rat liver microsomes.