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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.
AuthorsWataru Hamaguchi, Naoyuki Masuda, Satoshi Miyamoto, Shigetoshi Kikuchi, Fumie Narazaki, Yasuhiro Shiina, Ryushi Seo, Yasushi Amano, Takuma Mihara, Hiroyuki Moriguchi, Kouji Hattori
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 13 Pg. 3351-67 (Jul 01 2015) ISSN: 1464-3391 [Electronic] England
PMID25960322 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Ltd. All rights reserved.
Chemical References
  • Antipsychotic Agents
  • Benzimidazoles
  • Hallucinogens
  • Phosphodiesterase Inhibitors
  • Pyridines
  • Quinolines
  • PDE10A protein, human
  • Phosphoric Diester Hydrolases
  • Phencyclidine
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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