title: 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).
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%.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Wenthur
authors.forename: Ryan
authors.initials: R
authors.lastname: Morrison
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Felts
authors.forename: Katrina A
authors.initials: KA
authors.lastname: Smith
authors.forename: Julie L
authors.initials: JL
authors.lastname: Engers
authors.forename: Frank W
authors.initials: FW
authors.lastname: Byers
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Emmitte
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: C583163:(R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl)(3-hydroxypiperidin-1-yl)methanone; D010880:Piperidines; D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3