title: Synthesis and in vitro characterization of cinnoline and benzimidazole analogues as phosphodiesterase 10A inhibitors.
abstract: Fifteen cinnoline analogues and six benzimidazole phosphodiesterase 10A (PDE10A) inhibitors were synthesized as potential PET radiopharmaceuticals and their in vitro activity as PDE10A inhibitors was determined. Nine out of twenty-one compounds were potent inhibitors of PDE10A with IC50 values ranging from 1.5 to 18.6nM. Notably, the IC50 values of compounds 26a, 26b, and 33c were 1.52±0.18, 2.86±0.10, and 3.73±0.60nM, respectively; these three compounds also showed high in vitro selectivity (>1000-fold) for PDE10A over PDE 3A/3B, PDE4A/4B. The high potency and selectivity of these three compounds suggests that they could be radiolabeled with PET radionuclides for further evaluation of their in vivo pharmacological behavior and ability to quantify PDE10A in the brain.
authors.affiliation: Department of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Francis N
authors.initials: FN
authors.lastname: Murigi
authors.affiliation: Department of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United States. Electronic address: tuz@mir.wustl.edu.
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology*; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*
chemical_list: D001562:Benzimidazoles; D006574:Heterocyclic Compounds, 2-Ring; D010726:Phosphodiesterase Inhibitors; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases; C476282:cinnoline
keywords: Benzimidazole analogues; Cinnoline analogues; PET; Phosphodiesterase 10A