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

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• 作者：Jose Mar铆a Cid ; Gary Tresadern ; Juan Antonio Vega ; Ana Isabel de Lucas ; Encarnaci贸n Matesanz ; Laura Iturrino ; Mar铆a Lourdes Linares ; Ar谩nzazu Garcia ; Jos茅 Ignacio Andr茅s ; Gregor J. Macdonald ; Daniel Oehlrich ; Hilde Lavreysen ; Anton Megens ; Abdellah Ahnaou ; Wilhelmus Drinkenburg ; Claire Mackie ; Stefan Pype ; David Gallacher ; Andr茅s A. Trabanco
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 25, 2012
• 年：2012
• 卷：55
• 期：20
• 页码：8770-8789
• 全文大小：742K
• 年卷期：v.55,no.20(October 25, 2012)
• ISSN：1520-4804

文摘

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鈥搘ake 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.