SAR study of a subtype selective allosteric potentiator of metabotropic glutamate 2 receptor, N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide.
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.
Barda
David A
DA
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, IN 46285, USA. barda@lilly.com
Wang
Zhao-Qing
ZQ
Britton
Thomas C
TC
Henry
Steven S
SS
Jagdmann
G Erik
GE
Coleman
Darrell S
DS
Johnson
Michael P
MP
Andis
Sherri L
SL
Schoepp
Darryle D
DD
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
C476435:N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D013449:Sulfonamides; C108822:metabotropic glutamate receptor 2