Fluorine‐Containing 6, 7‐Dialkoxybiaryl‐Based Inhibitors for Phosphodiesterase 10 A: Synthesis and in vitro Evaluation of Inhibitory Potency, Selectivity, and Metabolism. Issue 7 (11th April 2014)

• Record Type: Journal Article
• Authors: Schwan, Gregor; Barbar Asskar, Ghadir; Höfgen, Norbert; Kubicova, Lenka; Funke, Uta; Egerland, Ute; Zahn, Michael; Nieber, Karen; Scheunemann, Matthias; Sträter, Norbert; Brust, Peter; Briel, Detlef
• Is Part Of: ChemMedChem. Volume 9:Issue 7(2014:Jul.)
• Page Start: 1476
• Page End: 1487
• Publication Date: 2014-04-11
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201300522
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 (<italic>R</italic>)‐7‐(fluoromethoxy)‐6‐methoxy‐4‐(3‐(quinoxaline‐2‐yloxy)pyrrolidine‐1‐yl)quinazoline (<bold>16 a</bold>), <bold>19 a</bold>–<bold>d</bold>, (<italic>R</italic>)‐<italic>tert</italic>‐butyl‐3‐(6‐fluoroquinoxalin‐2‐yloxy)pyrrolidine‐1‐carboxylate (<bold>29</bold>), and <bold>35</bold> (IC<sub>50</sub> PDE10A 11–65 n<sc>M</sc>) 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.</p> </abstract>