Chemical & Pharmacokinetic Sciences, Lundbeck Research USA, Paramus, NJ 07652, USA.
Bioorg Med Chem Lett. 2012 Oct 15;22(20):6469-74. doi: 10.1016/j.bmcl.2012.08.044. Epub 2012 Aug 25.
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.
鉴定出一系列新型芳基氮杂环丁基恶二唑类化合物作为 mGluR5 正变构调节剂 (PAM)，具有改善的物理化学性质。N-取代环己基和外-降冰片基羧酰胺，以及氮杂环丁烷的氨基甲酸酯类似物是中等至强效的 mGluR5 PAM。氮杂环丁烷的芳基、低级烷基羧酰胺类似物和磺酰胺类似物是中等强度的 mGluR5 负变构调节剂 (NAM)。在氮杂环丁二唑部分，间位的氟、氯和甲基等取代基是可以耐受的，而对位取代基则导致化合物失活或成为 NAMs。与类似物的紧密药效基团和微妙的“PAM 到 NAM 转换”使得该系列的优化极具挑战性。
