Fluorine-containing 6,7-dialkoxybiaryl-based inhibitors for phosphodiesterase 10 A: synthesis and in vitro evaluation of inhibitory potency, selectivity, and metabolism

Gregor Schwan, Ghadir Barbar Asskar, Norbert Höfgen, Lenka Kubicova, Uta Funke, Ute Egerland, Michael Zahn, Karen Nieber, Matthias Scheunemann, Norbert Sträter, Peter Brust, Detlef Briel

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)1476-1487
Number of pages12
JournalChemMedChem
Volume9
Issue number7
Early online date11 Apr 2014
DOIs
Publication statusPublished - 1 Jul 2014

Keywords

  • 3D QSAR
  • drug design
  • fluorine
  • phosphodiesterase 10 A
  • quinazolines

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