title: SAR study of a subtype selective allosteric potentiator of metabotropic glutamate 2 receptor, N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide.
abstract: The major excitatory neurotransmitter in the Central Nervous System is L-glutamic acid. As a result much attention has been given to the discovery of selective modulators of both the ionotropic glutamate receptors (iGluRs) and the metabotropic glutamate receptors (mGluRs). In this study we describe a novel class of subtype selective allosteric potentiators of the mGlu2 receptor. An active compound N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide, LY181837, was identified in the course of compound screening. The synthesis of two series of analogs examined the structural requirements of the diaryl region of this compound. This SAR study also resulted in compounds with an increase in potency of over 100-fold where the most potent compound reported has EC(50)=14 nM.
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, IN 46285, USA. barda@lilly.com
authors.forename: David A
authors.initials: DA
authors.lastname: Barda
authors.forename: Zhao-Qing
authors.initials: ZQ
authors.lastname: Wang
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Britton
authors.forename: Steven S
authors.initials: SS
authors.lastname: Henry
authors.forename: G Erik
authors.initials: GE
authors.lastname: Jagdmann
authors.forename: Darrell S
authors.initials: DS
authors.lastname: Coleman
authors.forename: Michael P
authors.initials: MP
authors.lastname: Johnson
authors.forename: Sherri L
authors.initials: SL
authors.lastname: Andis
authors.forename: Darryle D
authors.initials: DD
authors.lastname: Schoepp
mesh_terms: D000818:Animals; D011725:Pyridines / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C476435:N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D013449:Sulfonamides; C108822:metabotropic glutamate receptor 2