Synthesis and preliminary biological evaluation of potent and selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility

Robert M. Rzasa, Michael J. Frohn, Kristin L. Andrews, Samer Chmait, Ning Chen, Jeffrey G. Clarine, Carl Davis, Heather A. Eastwood, Daniel B. Horne, Essa Hu, Adrie D. Jones, Matthew R. Kaller, Roxanne K. Kunz, Silke Miller, Holger Monenschein, Thomas Nguyen, Alexander J. Pickrell, Amy Porter, Andreas Reichelt, Xiaoning ZhaoJames J.S. Treanor, Jennifer R. Allen

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

We report the discovery of a novel series of 2-(3-alkoxy-1-azetidinyl) quinolines as potent and selective PDE10A inhibitors. Structure-activity studies improved the solubility (pH 7.4) and maintained high PDE10A activity compared to initial lead compound 3, with select compounds demonstrating good oral bioavailability. X-ray crystallographic studies revealed two distinct binding modes to the catalytic site of the PDE10A enzyme. An ex vivo receptor occupancy assay in rats demonstrated that this series of compounds covered the target within the striatum.

Original languageEnglish
Pages (from-to)6570-6585
Number of pages16
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number23
DOIs
StatePublished - 1 Dec 2014
Externally publishedYes

Keywords

  • Azetidine
  • Inhibitors
  • PDE10A
  • Phosphodiesterase
  • Schizophrenia

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