title: Synthesis and in vivo evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors.
abstract: A novel class of phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability in mouse liver microsomes were designed and synthesized starting from 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline (MP-10). Replacement of the phenoxymethyl part of MP-10 with an oxymethyl phenyl unit led to the identification of 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (14), which showed moderate PDE10A inhibitory activity with improved metabolic stability in mouse and human liver microsomes over MP-10. Compound 14 showed high concentrations in plasma and brain after intraperitoneal administration and dose-dependently attenuated the hyperlocomotion induced by phencyclidine in mice, and oral administration of 14 (0.1, 0.3 mg/kg) also improved visual-recognition memory impairment in mice.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc.
authors.forename: Wataru
authors.initials: W
authors.lastname: Hamaguchi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Masuda
authors.forename: Kiyohiro
authors.initials: K
authors.lastname: Samizu
authors.forename: Takuma
authors.initials: T
authors.lastname: Mihara
authors.forename: Kaori
authors.initials: K
authors.lastname: Takama
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases; D010622:Phencyclidine