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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.

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.

Rombouts F.J.R.,Neuroscience Medicinal Chemistry | Tresadern G.,Discovery science | Buijnsters P.,Neuroscience Medicinal Chemistry | Langlois X.,Janssen Pharmaceutical | And 6 more authors.
ACS Medicinal Chemistry Letters | Year: 2015

A novel series of pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and in vivo receptor occupancy data are given for two representative compounds 6 and 12. © 2015 American Chemical Society.

Wager T.T.,Neuroscience Medicinal Chemistry | Wager T.T.,Pfizer | Chandrasekaran R.Y.,Neuroscience Medicinal Chemistry | Hou X.,Neuroscience Medicinal Chemistry | And 4 more authors.
ACS Chemical Neuroscience | Year: 2010

As part of our effort to increase survival of drug candidates and to move our medicinal chemistry design to higher probability space for success in the Neuroscience therapeutic area, we embarked on a detailed study of the property space for a collection of central nervous system (CNS) molecules. We carried out a thorough analysis of properties for 119 marketed CNS drugs and a set of 108 Pfizer CNS candidates. In particular, we focused on understanding the relationships between physicochemical properties, in vitro ADME (absorption, distribution, metabolism, and elimination) attributes, primary pharmacology binding efficiencies, and in vitro safety data for these two sets of compounds. This scholarship provides guidance for the design of CNS molecules in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic. © 2010 American Chemical Society.

Henderson J.L.,Neuroscience Medicinal Chemistry | Sawant-Basak A.,Neuroscience Medicinal Chemistry | Tuttle J.B.,Neuroscience Medicinal Chemistry | Dounay A.B.,Neuroscience Medicinal Chemistry | And 17 more authors.
MedChemComm | Year: 2013

A series of kynurenine aminotransferase II (KAT II) inhibitors has been developed replacing the hydroxamate motif with a bioisostere. Triazolinones or triazoles have proven to be effective replacements with significantly improved pharmacokinetics including reduced clearance and increased bioavailability. An X-ray crystal structure of an inhibitor bound in KAT II confirms that the irreversible binding to the co-factor is maintained and that the heterocycles make productive hydrogen bonds to the arginine-399. © The Royal Society of Chemistry 2013.

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