Discovery of 1-Buty1-3-chloro-4-(4-pheny1-1-piperidiny1)(1H)-pyridone (JNJ-40411813): A Novel Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor

作者：Maria Cid Jose; Tresadern Gary; Duvey Guillaume; Lutjens Robert; Finn Terry; Rocher Jean Philippe; Poli Sonia; Antonio Vega Juan; Isabel de Lucas Ana; Matesanz Encarnacion; Lourdes Linares Maria; Ignacio Andres Jose; Alcazar Jesus; Manuel Alonso Jose; Macdonald Gregor J; Oehlrich Daniel; Lavreysen Hilde; Ahnaou Abdelah; Drinkenburg Wilhelmus; Mackie Claire; Pype Stefan; Gallacher David; Trabanco Andres A

来源：Journal of Medicinal Chemistry, 2014, 57(15): 6495-6512.

DOI：10.1021/jm500496m

We previously reported the discovery of 4-aryl-substituted pyridones with mGlu2 PAM activity starting from the HTS hit S. 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.

• 出版日期2014-8-14