Discovery
of (<i>R</i>)‑(2-Fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-Hydroxypiperidin-1-yl)methanone (ML337), An mGlu<sub>3</sub> Selective
and CNS Penetrant Negative Allosteric Modulator (NAM)
- Publication date
- Publisher
Abstract
A multidimensional,
iterative parallel synthesis effort identified a series of highly
selective mGlu<sub>3</sub> NAMs with submicromolar potency and good CNS penetration.
Of these, ML337 resulted (mGlu<sub>3</sub> IC<sub>50</sub> = 593 nM,
mGlu<sub>2</sub> IC<sub>50</sub> >30 μM) with B:P ratios
of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to
the incorporation of deuterium atoms to address a metabolic soft spot,
which subsequently lowered both in vitro and in vivo clearance by
>50%