4XY2

Crystal structure of PDE10A in complex with ASP9436

Summary for 4XY2

• Entry DOI: 10.2210/pdb4xy2/pdb
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: phosphodiesterase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 79817.77

Authors

Amano, Y.,Honbou, K. (deposition date: 2015-02-02, release date: 2015-06-17, Last modification date: 2024-03-20)

Primary citation

Hamaguchi, W.,Masuda, N.,Miyamoto, S.,Kikuchi, S.,Narazaki, F.,Shiina, Y.,Seo, R.,Amano, Y.,Mihara, T.,Moriguchi, H.,Hattori, K.
Addressing phototoxicity observed in a novel series of biaryl derivatives: Discovery of potent, selective and orally active phosphodiesterase 10A inhibitor ASP9436
Bioorg.Med.Chem., 23:3351-3367, 2015

PubMed 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.

PubMed: 25960322
DOI: 10.1016/j.bmc.2015.04.052

Experimental method

X-RAY DIFFRACTION (2.03 Å)