Addressing phototoxicity observed in a novel series of biaryl derivatives: Discovery of potent, selective and orally active phosphodiesterase 10A inhibitor ASP9436. Issue 13 (1st July 2015)

• Record Type: Journal Article
• Authors: Hamaguchi, Wataru; Masuda, Naoyuki; Miyamoto, Satoshi; Kikuchi, Shigetoshi; Narazaki, Fumie; Shiina, Yasuhiro; Seo, Ryushi; Amano, Yasushi; Mihara, Takuma; Moriguchi, Hiroyuki; Hattori, Kouji
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 13(2015)
• Page Start: 3351
• Page End: 3367
• Publication Date: 2015-07-01
• Subjects: Schizophrenia -- PDE10A inhibitor -- Phototoxicity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.04.052
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: We synthesized several biaryl derivatives as PDE10A inhibitors to prevent phototoxicity of 2-[4-({[1-methyl-4-(pyridin-4-yl)-1 H -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 of1 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-1 H -benzimidazol-4-yl)phenoxy]methyl}-1 H -pyrazol-4-yl)pyridin-2(1 H )-one (38b ). Compound38b exhibited good selectivity against other PDEs, and oral administration of38b improved visual-recognition memory deficit in mice at doses of 0.001 and 0.003 mg/kg in the novel object recognition test. ASP9436 (sesquiphosphate of38b ) may therefore be used for the treatment of schizophrenia with a low risk of phototoxicity.