Addressing phototoxicity observed in a novel series of biaryl derivatives discovery of potent, selective and orally active phosphodiesterase 10A inhibitor ASP9436.
We synthesized several biaryl derivatives as PDE10A inhibitors to prevent phototoxicity of 2-4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yloxymethyl)phenylquinoline (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)phenoxymethyl-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 0.003mgkg 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.