Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead |
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| Authors: | Richard Williams Colleen M Niswender Qingwei Luo Uyen Le P Jeffrey Conn Craig W Lindsley |
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| Institution: | 1. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;2. Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN 37232, USA;3. Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA |
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| Abstract: | 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. |
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