title: Identification of a novel orally bioavailable phosphodiesterase 10A (PDE10A) inhibitor with efficacy in animal models of schizophrenia.
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.
authors.affiliation: Neuroscience Medicinal Chemistry and ‡Discovery Sciences Analytical Chemistry, Janssen Research & Development , Calle Jarama 75, Polígono Industrial, Toledo 45007, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Bartolomé-Nebreda
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Alonso de Diego
authors.forename: Marta
authors.initials: M
authors.lastname: Artola
authors.forename: Francisca
authors.initials: F
authors.lastname: Delgado
authors.forename: Óscar
authors.initials: Ó
authors.lastname: Delgado
authors.forename: María Luz
authors.initials: ML
authors.lastname: Martín-Martín
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Martínez-Viturro
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Pena
authors.forename: Han Min
authors.initials: HM
authors.lastname: Tong
authors.forename: Michiel
authors.initials: M
authors.lastname: Van Gool
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Alonso
authors.forename: Alberto
authors.initials: A
authors.lastname: Fontana
authors.forename: Gregor J
authors.initials: GJ
authors.lastname: Macdonald
authors.forename: Anton
authors.initials: A
authors.lastname: Megens
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.forename: Marijke
authors.initials: M
authors.lastname: Somers
authors.forename: Greet
authors.initials: G
authors.lastname: Vanhoof
authors.forename: Susana
authors.initials: S
authors.lastname: Conde-Ceide
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004195:Disease Models, Animal; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases; D051381:Rats; D017208:Rats, Wistar; D012559:Schizophrenia / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D010726:Phosphodiesterase Inhibitors; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases