title: Synthesis and preliminary biological evaluation of potent and  selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A  inhibitors with improved solubility.
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.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. Electronic address: rrzasa@amgen.com.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Rzasa
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Frohn
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Andrews
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Samer
authors.initials: S
authors.lastname: Chmait
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Clarine
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Davis
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Eastwood
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Horne
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Essa
authors.initials: E
authors.lastname: Hu
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., 1120 Veterans Boulevard, So San Francisco, CA 94080-1985, USA.
authors.forename: Adrie D
authors.initials: AD
authors.lastname: Jones
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Kaller
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Roxanne K
authors.initials: RK
authors.lastname: Kunz
authors.affiliation: Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Silke
authors.initials: S
authors.lastname: Miller
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Holger
authors.initials: H
authors.lastname: Monenschein
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Pickrell
authors.affiliation: Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Porter
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reichelt
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., 1120 Veterans Boulevard, So San Francisco, CA 94080-1985, USA.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: James J S
authors.initials: JJS
authors.lastname: Treanor
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Allen
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases