title: Synthesis, SAR study, and biological evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors with reduced CYP3A4 inhibition.
abstract: A novel class of phosphodiesterase 10A inhibitors with potent PDE10A inhibitory activity and reduced CYP3A4 inhibition was designed and synthesized starting from 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1). Replacement of pyridine ring of 1 with N-methyl pyridone ring drastically improved CYP3A4 inhibition, and further optimization of these quinoline analogues identified 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (42b), which showed potent PDE10A inhibitory activity and a good CYP3A4 inhibition profile. A PET study with (11)C-labeled 42b indicated that 42b exhibited good brain penetration and specifically accumulated in the rodent striatum. Further, oral administration of 42b dose-dependently attenuated phencyclidine-induced hyperlocomotion in mice with an ED50 value of 2.0mg/kg and improved visual-recognition memory impairment at 0.1 and 0.3mg/kg in mice novel object recognition test.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. Electronic address: wataru.hamaguchi@astellas.com.
authors.forename: Wataru
authors.initials: W
authors.lastname: Hamaguchi
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Masuda
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shiina
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Kikuchi
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Mihara
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Moriguchi
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fushiki
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Amano
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Honbou
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Hattori
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D009043:Motor Activity / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D049268:Positron-Emission Tomography; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D011994:Recombinant Proteins; C037219:quinoline; D051544:Cytochrome P-450 CYP3A; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: CYP3A4 inhibition; PDE10A inhibitor; Quinoline; Schizophrenia