Discovery of 3-Cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl[1,2,4]t riazolo[4,3-a]pyridine (JNJ-42153605): A Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor

作者：Maria Cid Jose; Tresadern Gary; Antonio Vega Juan; Isabel de Lucas Ana; Matesanz Encarnacion; Iturrino Laura; Lourdes Linares Maria; Garcia Aranzazu; Ignacio Andres Jose; Macdonald Gregor J; Oehlrich Daniel; Lavreysen Hilde; Megens Anton; Ahnaou Abdellah; Drinkenburg Wilhelmus; Mackie Claire; Pype Stefan; Gallacher David; Trabanco Andres A

来源：Journal of Medicinal Chemistry, 2012, 55(20): 8770-8789.

DOI：10.1021/jm3010724

Advanced leads from a series of 1,2,4-triazolo[4,3-a]pyridines with mGlu2 receptor PAM activity are reported. By modification of the analogous imidazo[1,2-a]pyridine series, the newly reported leads have improved potency, in vitro ADMET, and hERG as well as good in vivo PK profile. The optimization of the series focused on improving metabolic stability while controlling lipophilicity by introducing small modifications to the scaffold substituents. Analysis of this series combined with our previously reported mGlu2 receptor PAMs showed how lipophilic ligand efficiency was improved during the course of the program. Among the best compounds, example 20 (JNJ-42153605) showed a central in vivo efficacy by inhibition of REM sleep state at a dose of 3 mg/kg po in the rat sleep-wake EEG paradigm, a phenomenon shown earlier to be mGlu2 mediated. In mice, compound 20 reversed PCP-induced hyperlocomotion with an ED50 of 5.4 mg/kg sc, indicative of antipsychotic activity.

• 出版日期2012-10-25