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)

  • J Med Chem. 2013 Jun 27;56(12):5208-12. doi: 10.1021/jm400439t.
Cody J Wenthur  1 ,  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
Affiliations
  • 1. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
PMID: 23718281 DOI: 10.1021/jm400439t
Abstract

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%.

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