Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM)

Cody J. Wenthur, Ryan Morrison, Andrew S. Felts, Katrina A. Smith, Julie L. Engers, Frank W. Byers, J. Scott Daniels, Kyle A. Emmitte, P. Jeffrey Conn, Craig W. Lindsley

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A multidimensional, iterative parallel synthesis effort identified a series of highly selective mGlu3 NAMs with submicromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu3 IC50 = 593 nM, mGlu2 IC50 >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%.

Original languageEnglish
Pages (from-to)5208-5212
Number of pages5
JournalJournal of Medicinal Chemistry
Issue number12
StatePublished - 27 Jun 2013


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