Identification of a novel orally bioavailable phosphodiesterase 10A (PDE10A) inhibitor with efficacy in animal models of schizophrenia.

作者信息

Bartolomé-Nebreda José Manuel, Alonso de Diego Sergio A, Artola Marta, Delgado Francisca, Delgado Óscar, Martín-Martín María Luz, Martínez-Viturro Carlos M, Pena Miguel Ángel, Tong Han Min, Van Gool Michiel, Alonso José Manuel, Fontana Alberto, Macdonald Gregor J, Megens Anton, Langlois Xavier, Somers Marijke, Vanhoof Greet, Conde-Ceide Susana

机构信息

Neuroscience Medicinal Chemistry and ‡Discovery Sciences Analytical Chemistry, Janssen Research & Development , Calle Jarama 75, Polígono Industrial, Toledo 45007, Spain.

出版信息

J Med Chem. 2015 Jan 22;58(2):978-93. doi: 10.1021/jm501651a. Epub 2015 Jan 12.

DOI:10.1021/jm501651a

PMID:25495129

Abstract

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.

摘要

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