Fluorine containing 6,7-dialkoxybiaryl-based inhibitors for phosphodiesterase 10A: Synthesis and in vitro evaluation of inhibition potency, selectivity and metabolism


Fluorine containing 6,7-dialkoxybiaryl-based inhibitors for phosphodiesterase 10A: Synthesis and in vitro evaluation of inhibition potency, selectivity and metabolism

Schwan, G.; Asskar, G. B.; Höfgen, N.; Kubicova, L.; Funke, U.; Egerland, U.; Zahn, M.; Nieber, K.; Scheunemann, M.; Sträter, N.; Brust, P.; Briel, D.

Based on the potent phosphodiesterase 10A (PDE10A) inhibitor PQ-10, we have synthesised thirty-two derivatives to determine relationships between their molecular structure and binding properties. Their roles as potential positron emission tomography (PET) ligands as well as the inhibitory potency to PDE10A and other PDEs have been evaluated and the metabolic stability has been determined in vitro. According to our findings, halogenalkyl substituents at position 2 of the quinazoline moiety and/or halogenalkyloxy substituents at position 6 or 7 affect not only the compounds' affinity, but also their selectivity. As a result of substituting the methoxy group for a monofluoroethoxy or difluoroethoxy group (19d and 19c) at position 6 of the quinazoline ring, the selectivity to PDE10A primarily increased compared to PDE3A. The same result was obtained by 6,7-difluoride substitution on the quinoxaline moiety (35). Finally, the fluorinated compounds 16a, 19a-d, 29 and 35 (IC50 PDE10A 11-65 nM) showed the highest inhibitory potential. Further, fluoroethoxy substitution at position 7 of the quinazoline ring improved metabolic stability in comparison to the lead structure, PQ-10.

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Publ.-Id: 19062