title: Fluorine-containing 6,7-dialkoxybiaryl-based inhibitors for phosphodiesterase 10 A: synthesis and in vitro evaluation of inhibitory potency, selectivity, and metabolism.
abstract: Based on the potent phosphodiesterase 10 A (PDE10A) inhibitor PQ-10, we synthesized 32 derivatives to determine relationships between their molecular structure and binding properties. Their roles as potential positron emission tomography (PET) ligands were evaluated, as well as their inhibitory potency toward PDE10A and other PDEs, and their metabolic stability was determined in vitro. According to our findings, halo-alkyl substituents at position 2 of the quinazoline moiety and/or halo-alkyloxy substituents at positions 6 or 7 affect not only the compounds' affinity, but also their selectivity toward PDE10A. As a result of substituting the methoxy group for a monofluoroethoxy or difluoroethoxy group at position 6 of the quinazoline ring, the selectivity for PDE10A over PDE3A increased. The same result was obtained by 6,7-difluoride substitution on the quinoxaline moiety. Finally, fluorinated compounds (R)-7-(fluoromethoxy)-6-methoxy-4-(3-(quinoxaline-2-yloxy)pyrrolidine-1-yl)quinazoline (16 a), 19 a-d, (R)-tert-butyl-3-(6-fluoroquinoxalin-2-yloxy)pyrrolidine-1-carboxylate (29), and 35 (IC50 PDE10A 11-65 nM) showed the highest inhibitory potential. Further, fluoroethoxy substitution at position 7 of the quinazoline ring improved metabolic stability over that of the lead structure PQ-10.
authors.affiliation: Institut für Pharmazie, Universität Leipzig, Brüderstr. 34, 04103 Leipzig (Germany), Fax: (+49) 341 9736889.
authors.forename: Gregor
authors.initials: G
authors.lastname: Schwan
authors.forename: Ghadir
authors.initials: G
authors.lastname: Barbar Asskar
authors.forename: Norbert
authors.initials: N
authors.lastname: Höfgen
authors.forename: Lenka
authors.initials: L
authors.lastname: Kubicova
authors.forename: Uta
authors.initials: U
authors.lastname: Funke
authors.forename: Ute
authors.initials: U
authors.lastname: Egerland
authors.forename: Michael
authors.initials: M
authors.lastname: Zahn
authors.forename: Karen
authors.initials: K
authors.lastname: Nieber
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheunemann
authors.forename: Norbert
authors.initials: N
authors.lastname: Sträter
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.forename: Detlef
authors.initials: D
authors.lastname: Briel
mesh_terms: D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008297:Male; D062105:Molecular Docking Simulation; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D051381:Rats
chemical_list: D008024:Ligands; D010726:Phosphodiesterase Inhibitors; D011799:Quinazolines; D005461:Fluorine; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: 3D QSAR; drug design; fluorine; phosphodiesterase 10 A; quinazolines