Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead.

@article{Williams2009PositiveAM,
  title={Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead.},
  author={Richard T. Williams and Colleen M Niswender and Qingwei Luo and Uyen N Le and P Jeffrey Conn and Craig W Lindsley},
  journal={Bioorganic & medicinal chemistry letters},
  year={2009},
  volume={19 3},
  pages={962-6}
}
This Letter describes the synthesis and SAR of two mGluR4 positive allosteric modulator leads, 6 and 7. VU001171 (6) represents the most potent (EC(50)=650 nM), efficacious (141% Glu Max) and largest fold shift (36-fold) of any mGluR4 PAM reported to date. However, this work highlights the challenges in hit-to-lead for mGluR4 PAMs, with multiple confirmed HTS hits displaying little or no tractable SAR.