title: Fused thiazolyl alkynes as potent mGlu5 receptor positive allosteric modulators.
abstract: A new series of potent fused thiazole mGlu5 receptor positive allosteric modulators (PAMs) (10, 11 and 27-31) are disclosed and details of the SAR and optimization are described. Optimization of alkynyl thiazole 9 (Lu AF11205) led to the identification of potent fused thiazole analogs 10b, 27a, 28j and 31d. In general, substituted cycloalkyl, aryl and heteroaryl carboxamides, and carbamate analogs are mGlu5PAMs, whereas smaller alkyl carboxamide, sulfonamide and sulfamide analogs tend to be mGlu5 negative allosteric modulators (NAMs).
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA. packiara@yahoo.com
authors.forename: Mathivanan
authors.initials: M
authors.lastname: Packiarajan
authors.forename: Michel
authors.initials: M
authors.lastname: Grenon
authors.forename: Samuel
authors.initials: S
authors.lastname: Zorn
authors.forename: Allen T
authors.initials: AT
authors.lastname: Hopper
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: D000480:Alkynes / Q000737:chemistry*; D000494:Allosteric Regulation; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D064529:Receptor, Metabotropic Glutamate 5 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000480:Alkynes; D000577:Amides; D002219:Carbamates; D064529:Receptor, Metabotropic Glutamate 5; D013844:Thiazoles