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
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- 作者：Jos茅 Mar铆a Cid ; Gary Tresadern ; Guillaume Duvey ; Robert L眉tjens ; Terry Finn ; Jean-Philippe Rocher ; Sonia Poli ; Juan Antonio Vega ; Ana Isabel de Lucas ; Encarnaci贸n Matesanz ; Mar铆a Lourdes Linares ; Jos茅 Ignacio Andr茅s ; Jes煤s Alcazar ; Jos茅 Manuel Alonso ; Gregor J. Macdonald ; Daniel Oehlrich ; Hilde Lavreysen ; Abdelah Ahnaou ; Wilhelmus Drinkenburg ; Claire Mackie ; Stefan Pype ; David Gallacher ; Andr茅s A. Trabanco
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：August 14, 2014
- 年：2014
- 卷：57
- 期：15
- 页码：6495-6512
- 全文大小：729K
- ISSN：1520-4804
文摘
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.