In this study, we report the identification of potent pyrimidoindazoles as phosphodiesterase10A (PDE10A) inhibitors by using the method of fragment-based drug discovery (FBDD). The pyrazolopyridine derivative 2 was found to be a fragment hit compound which could occupy a part of the binding site of PDE10A enzyme by using the method of the X-ray co-crystal structure analysis. On the basis of the crystal structure of compound 2 and PDE10A protein, a number of compounds were synthesized and evaluated, by means of structure-activity relationship (SAR) studies, which culminated in the discovery of a novel pyrimidoindazole derivative 13 having good physicochemical properties.
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Chino, A., Seo, R., Amano, Y., Namatame, I., Hamaguchi, W., Honbou, K., … Masuda, N. (2018). Fragment-based discovery of pyrimido[1,2-B]indazole PDE10A inhibitors. Chemical and Pharmaceutical Bulletin, 66(3), 286–294. https://doi.org/10.1248/cpb.c17-00836