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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Selectivity mechanism of inhibition towards Phosphodiesterase 1B and phosphodiesterase 10A in silico investigation.
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Due to the unclear selectivity of the protein system, designing selective small molecule inhibitors has been a significant challenge. This issue is particularly prominent in the phosphodiesterases (PDEs) system. Phosphodiesterase 1B (PDE1B) and phosphodiesterase 10 A (PDE10A) are two closely related subtypes of PDE proteins that play diverse roles in the immune system and tumorigenesis, respectively.
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