Referenced in: none

Automatically associated channels: Kv11.1

Title: Discovery of 1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone (JNJ-40411813): a novel positive allosteric modulator of the metabotropic glutamate 2 receptor.

Authors: Jose María Cid, Gary Tresadern, Guillaume Duvey, Robert Lutjens, Terry Finn, Jean-Philippe Rocher, Sonia Poli, Juan Antonio Vega, Ana Isabel de Lucas, Encarnación Matesanz, María Lourdes Linares, José Ignacio Andrés, Jesús Alcazar, José Manuel Alonso, Gregor J Macdonald, Daniel Oehlrich, Hilde Lavreysen, Abdelah Ahnaou, Wilhelmus Drinkenburg, Claire Mackie, Stefan Pype, David Gallacher, Andrés A Trabanco

Journal, date & volume: J. Med. Chem., 2014 Aug 14 , 57, 6495-512

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25032784

Abstract
We previously reported the discovery of 4-aryl-substituted pyridones with mGlu2 PAM activity starting from the HTS hit 5. In this article, we describe a different exploration from 5 that led to the discovery of a novel subseries of phenylpiperidine-substituted pyridones. The optimization strategy involved the introduction of different spacers between the pyridone core and the phenyl ring of 5. The fine tuning of metabolism and hERG followed by differentiation of advanced leads that were identified on the basis of PK profiles and in vivo potency converged on lead compound 36 (JNJ-40411813). Full in vitro and in vivo profiles indicate that 36 displayed an optimal interplay between potency, selectivity, favorable ADMET/PK and cardiovascular safety profile, and central EEG activity. Compound 36 has been investigated in the clinic for schizophrenia and anxious depression disorders.