title: Synthesis, SAR and unanticipated pharmacological profiles of analogues of the mGluR5 ago-potentiator ADX-47273.
abstract: An iterative analogue library synthesis strategy rapidly developed comprehensive SAR for the mGluR5 ago-potentiator ADX-47273. This effort identified key substituents in the 3-position of oxadiazole that engendered either mGluR5 ago-potentiation or pure mGluR5 positive allosteric modulation. The mGluR5 positive allosteric modulators identified possessed the largest fold shifts (up to 27.9-fold) of the glutamate CRC reported to date as well as providing improved physiochemical properties.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6600, USA.
authors.forename: Darren W
authors.initials: DW
authors.lastname: Engers
authors.forename: Alice L
authors.initials: AL
authors.lastname: Rodriguez
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: Alexis S
authors.initials: AS
authors.lastname: Hammond
authors.forename: Daryl
authors.initials: D
authors.lastname: Venable
authors.forename: Oluwatomi
authors.initials: O
authors.lastname: Oluwatola
authors.forename: Gary A
authors.initials: GA
authors.lastname: Sulikowski
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D020650:Combinatorial Chemistry Techniques; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D010069:Oxadiazoles; D010880:Piperidines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C533862:S-(4-fluorophenyl)-(3-(3-(4-fluorophenyl)-(1,2,4)-oxadiazol-5-yl)piperidin-1-yl)methanone