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

Williams R, Niswender CM, Luo Q, Le U, Conn PJ, Lindsley CW
Bioorg Med Chem Lett. 2009 19 (3): 962-6

PMID: 19097893 · PMCID: PMC3787871 · DOI:10.1016/j.bmcl.2008.11.104

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.

MeSH Terms (14)

Allosteric Regulation Allosteric Site Animals Chemistry, Pharmaceutical CHO Cells Cricetinae Cricetulus Dose-Response Relationship, Drug Drug Design Drug Evaluation, Preclinical Models, Chemical Molecular Conformation Receptors, Metabotropic Glutamate Structure-Activity Relationship

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