title: N-Aryl pyrrolidinonyl oxadiazoles as potent mGluR5 positive allosteric modulators.
abstract: A novel series of N-aryl pyrrolidinonyl oxadiazoles were identified as mGluR5 positive allosteric modulators (PAMs). Optimization of the initial lead compound 6a led to the identification of the 12c (-) enantiomer as a potent compound with acceptable in vitro clearance, CYP, hERG and PK properties. Para substituted N-aryl pyrrolidinonyl oxadiazoles are mGluR5 PAMs while the meta and ortho substituted N-aryl pyrrolidinonyl oxadiazoles are negative allosteric modulators (NAMs). Para fluoro substitution on the N-aryl group and meta chloro or methyl substituents on the aryl oxadiazole moiety are optimal for mGluR5 PAM efficacy. The existence of an exquisitely sensitive 'PAM to NAM switch' within this chemotype making it challenging for simultaneous optimization of potency and drug-like properties.
authors: Chemical & Pharmacokinetic Sciences, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA. packiara@yahoo.com
authors: Mathivanan
authors: M
authors: Packiarajan
authors: Christine G
authors: CG
authors: Mazza Ferreira
authors: Sang-Phyo
authors: SP
authors: Hong
authors: Andrew D
authors: AD
authors: White
authors: Gamini
authors: G
authors: Chandrasena
authors: Xiaosui
authors: X
authors: Pu
authors: Robbin M
authors: RM
authors: Brodbeck
authors: Albert J
authors: AJ
authors: Robichaud
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D002460:Cell Line; D006801:Humans; D010069:Oxadiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D010069:Oxadiazoles; D011759:Pyrrolidines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate