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)-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 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-1 H -benzimidazol-4-yl)phenoxy]methyl}-1 H -pyrazol-4-yl)pyridin-2(1 H )-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 0.003 mg/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.