Identification of a Novel Orally Bioavailable Phosphodiesterase 10A (PDE10A) Inhibitor with Efficacy in Animal Models of Schizophrenia

• Published in: Journal of medicinal chemistry 2015-01, Vol.58 (2), p.978-993
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological Availability; Disease Models, Animal; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - pharmacology; Phosphodiesterase Inhibitors - therapeutic use; Phosphoric Diester Hydrolases; Rats; Rats, Wistar; Schizophrenia - drug therapy; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm501651a

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.