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Basic Information

ID: ALA3351491

Journal: Bioorg Med Chem

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

Authors: Rzasa RM, Frohn MJ, Andrews KL, Chmait S, Chen N, Clarine JG, Davis C, Eastwood HA, Horne DB, Hu E, Jones AD, Kaller MR, Kunz RK, Miller S, Monenschein H, Nguyen T, Pickrell AJ, Porter A, Reichelt A, Zhao X, Treanor JJ, Allen JR.

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.

CiteXplore: 25456383

DOI: 10.1016/j.bmc.2014.10.013