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.
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Authors | Wataru Hamaguchi, Naoyuki Masuda, Satoshi Miyamoto, Shigetoshi Kikuchi, Fumie Narazaki, Yasuhiro Shiina, Ryushi Seo, Yasushi Amano, Takuma Mihara, Hiroyuki Moriguchi, Kouji Hattori |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 23
Issue 13
Pg. 3351-67
(Jul 01 2015)
ISSN: 1464-3391 [Electronic] England |
PMID | 25960322
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2015 Elsevier Ltd. All rights reserved. |
Chemical References |
- Antipsychotic Agents
- Benzimidazoles
- Hallucinogens
- Phosphodiesterase Inhibitors
- Pyridines
- Quinolines
- PDE10A protein, human
- Phosphoric Diester Hydrolases
- Phencyclidine
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Topics |
- Administration, Oral
- Animals
- Antipsychotic Agents
(administration & dosage, adverse effects, chemistry)
- Behavior, Animal
(drug effects)
- Benzimidazoles
(administration & dosage, adverse effects, chemistry)
- Binding Sites
- Crystallography, X-Ray
- Disease Models, Animal
- Hallucinogens
- Humans
- Male
- Mice
- Mice, Inbred ICR
- Pattern Recognition, Visual
(drug effects)
- Phencyclidine
- Phosphodiesterase Inhibitors
(administration & dosage, adverse effects, chemistry)
- Phosphoric Diester Hydrolases
(chemistry, metabolism)
- Photochemical Processes
- Protein Binding
- Pyridines
(administration & dosage, adverse effects, chemistry)
- Quinolines
(administration & dosage, adverse effects, chemistry)
- Schizophrenia
(chemically induced, drug therapy, enzymology, physiopathology)
- Ultraviolet Rays
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