Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1375695 | Bioorganic & Medicinal Chemistry Letters | 2009 | 5 Pages |
This Letter describes the synthesis and SAR of two mGluR4 positive allosteric modulator leads, 6 and 7. VU001171 (6) represents the most potent (EC50 = 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.
Graphical abstractThe synthesis and SAR of two mGluR4 positive allosteric modulator leads 6 and 7 is described. VU001171 (6) represents the most potent (EC50 = 650 nM), efficacious (141% Glu Max) and largest fold shift (36-fold) of any mGluR4 PAM ever described. However, this work highlights the challenges in hit-to-lead for mGluR4 PAMs, with multiple confirmed HTS hits displaying little or no tractable SAR.Figure optionsDownload full-size imageDownload as PowerPoint slide