title: Azetidinyl oxadiazoles as potent mGluR5 positive allosteric modulators.
abstract: A novel series of aryl azetidinyl oxadiazoles are identified as mGluR5 positive allosteric modulators (PAMs) with improved physico-chemical properties. N-substituted cyclohexyl and exo-norbornyl carboxamides, and carbamate analogs of azetidines are moderate to potent mGluR5 PAMs. The aryl, lower alkyl carboxamides analogs and sulfonamide analogs of azetidines are moderate mGluR5 negative allosteric modulators (NAMs). In the aryl oxadiazole moiety, substituents such as fluoro, chloro and methyl are well tolerated at the meta position while para substituents led to either inactive compounds or NAMs. A tight pharmacophore and subtle 'PAM to NAM switching' with close analogs makes the optimization of the series extremely challenging.
authors.affiliation: Chemical & Pharmacokinetic Sciences, Lundbeck Research USA, Paramus, NJ 07652, USA. packiara@yahoo.com
authors.forename: Mathivanan
authors.initials: M
authors.lastname: Packiarajan
authors.forename: Christine G Mazza
authors.initials: CG
authors.lastname: Ferreira
authors.forename: Sang-Phyo
authors.initials: SP
authors.lastname: Hong
authors.forename: Andrew D
authors.initials: AD
authors.lastname: White
authors.forename: Gamini
authors.initials: G
authors.lastname: Chandrasena
authors.forename: Xiaosui
authors.initials: X
authors.lastname: Pu
authors.forename: Robbin M
authors.initials: RM
authors.lastname: Brodbeck
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Robichaud
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D001384:Azetidines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D010069:Oxadiazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001384:Azetidines; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D010069:Oxadiazoles; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate