title: Synthesis and SAR of novel, non-MPEP chemotype mGluR5 NAMs identified by functional HTS.
abstract: This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype identified by a functional HTS approach. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and further examples of a mode of pharmacology 'switch' to provide PAMs with a non-MPEP scaffold.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhou
authors.forename: Alice L
authors.initials: AL
authors.lastname: Rodriguez
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays / Q000379:methods*; D015394:Molecular Structure; D010797:Phthalimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; C546444:3-(phthalimidyl)-N-(2-hydroxyphenyl)benzamide; D001549:Benzamides; D001562:Benzimidazoles; C546445:N-(3-(1H-benzo(d)imidazol-2-yl)-4-chlorophenyl)-5-bromofuran-2-carboxamide; D010797:Phthalimides; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C121465:6-methyl-2-(phenylethynyl)pyridine