Referenced in: none

Automatically associated channels: Kv11.1

Title: 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 receptor.

Authors: Jose María Cid, Gary Tresadern, Juan Antonio Vega, Ana Isabel de Lucas, Encarnación Matesanz, Laura Iturrino, María Lourdes Linares, Aránzazu García, José Ignacio Andrés, Gregor J Macdonald, Daniel Oehlrich, Hilde Lavreysen, Anton Megens, Abdellah Ahnaou, Wilhelmus Drinkenburg, Claire Mackie, Stefan Pype, David Gallacher, Andrés A Trabanco

Journal, date & volume: J. Med. Chem., 2012 Oct 25 , 55, 8770-89

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23072213

Abstract
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.