title: Discovery of imidazo[1,5-a]pyrido[3,2-e]pyrazines as a new class of phosphodiesterase 10A inhibitiors.
abstract: Novel imidazo[1,5-a]pyrido[3,2-e]pyrazines have been synthesized and characterized as both potent and selective phosphodiesterase 10A (PDE10A) inhibitors. For in vitro characterization, inhibition of PDE10A mediated cAMP hydrolysis was used and a QSAR model was established to analyze substitution effects. The outcome of this analysis was complemented by the crystal structure of PDE10A in complex with compound 49. Qualitatively new interactions between inhibitor and binding site were found, contrasting with previously published crystal structures of papaverine-like inhibitors. In accordance with the known antipsychotic potential of PDE10A inhibitors, MK-801 induced stereotypy and hyperactivity in rats were reversed by selected compounds. Thus, a promising compound class has been identified for the treatment of schizophrenia that could circumvent side effects connected with current therapies.
authors.affiliation: Biotie Therapies GmbH, Meissner Strasse 191, 01445 Radebeul, Germany. norbert.hoefgen@biotie.com
authors.forename: Norbert
authors.initials: N
authors.lastname: Höfgen
authors.forename: Hans
authors.initials: H
authors.lastname: Stange
authors.forename: Rudolf
authors.initials: R
authors.lastname: Schindler
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lankau
authors.forename: Christian
authors.initials: C
authors.lastname: Grunwald
authors.forename: Barbara
authors.initials: B
authors.lastname: Langen
authors.forename: Ute
authors.initials: U
authors.lastname: Egerland
authors.forename: Peter
authors.initials: P
authors.lastname: Tremmel
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: Karen L
authors.initials: KL
authors.lastname: Marquis
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hage
authors.forename: Boyd L
authors.initials: BL
authors.lastname: Harrison
authors.forename: Michael S
authors.initials: MS
authors.lastname: Malamas
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
authors.forename: Thomas
authors.initials: T
authors.lastname: Kronbach
mesh_terms: D000818:Animals; D055808:Drug Discovery / Q000379:methods*; D005260:Female; D006801:Humans; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017208:Rats, Wistar
chemical_list: D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases