title: Addressing phototoxicity observed in a novel series of biaryl derivatives: discovery of potent, selective and orally active phosphodiesterase 10A inhibitor ASP9436.
abstract: We synthesized several biaryl derivatives as PDE10A inhibitors to prevent phototoxicity of 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1) and found that the energy difference between the energy-minimized conformation and the coplanar conformation of the biaryl moiety helped facilitate prediction of the phototoxic potential of biaryl compounds. Replacement of the quinoline ring of 1 with N-methyl benzimidazole increased this energy difference and prevented phototoxicity in the 3T3 NRU test. Further optimization identified 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (38b). Compound 38b exhibited good selectivity against other PDEs, and oral administration of 38b improved visual-recognition memory deficit in mice at doses of 0.001 and 0.003mg/kg in the novel object recognition test. ASP9436 (sesquiphosphate of 38b) may therefore be used for the treatment of schizophrenia with a low risk of phototoxicity.
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: 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: Fumie
authors.initials: F
authors.lastname: Narazaki
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: Ryushi
authors.initials: R
authors.lastname: Seo
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: 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: Kouji
authors.initials: K
authors.lastname: Hattori
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry*; D001522:Behavior, Animal / Q000187:drug effects; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D006213:Hallucinogens; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010364:Pattern Recognition, Visual / Q000187:drug effects; D010622:Phencyclidine; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D055668:Photochemical Processes; D011485:Protein Binding; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry*; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry*; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D014466:Ultraviolet Rays
chemical_list: D014150:Antipsychotic Agents; D001562:Benzimidazoles; D006213:Hallucinogens; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011804:Quinolines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases; D010622:Phencyclidine
keywords: PDE10A inhibitor; Phototoxicity; Schizophrenia