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Beerse, Belgium

Cid J.M.,Janssen Cilag SAS | Tresadern G.,Janssen Cilag SAS | Duvey G.,Molecular science | Duvey G.,Addex Therapeutics | And 21 more authors.
Journal of Medicinal Chemistry | Year: 2014

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. © 2014 American Chemical Society. Source

Bartolome-Nebreda J.M.,Janssen Research and Development | Alonso De Diego S.A.,Janssen Research and Development | Artola M.,Janssen Research and Development | Delgado F.,Janssen Research and Development | And 14 more authors.
Journal of Medicinal Chemistry | Year: 2015

We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo[1,2-a]pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound 25a for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure-activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead 25a are described. © 2014 American Chemical Society. Source

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