A papaverine based pharmacophore model for PDE10A inhibition was generated via SBDD and used to design a library of 4-amino-6,7-dimethoxyquinazolines. From this library emerged an aryl ether pyrrolidyl 6,7-dimethoxyquinazoline series that became the focal point for additional modeling, X-ray, and synthetic efforts toward increasing PDE10A inhibitory potency and selectivity versus PDE3A/B. These efforts culminated in the discovery of 29, a potent and selective brain penetrable inhibitor of PDE10A.

中文翻译：

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发现了一系列6,7-二甲氧基-4-吡咯烷基喹唑啉PDE10A抑制剂。

通过SBDD生成了基于罂粟碱的PDE10A抑制药效团模型，并用于设计4-氨基-6,7-二甲氧基喹唑啉的文库。从该文库中出现了芳基醚吡咯烷基6,7-二甲氧基喹唑啉系列，该系列成为了其他建模，X射线和合成努力的重点，以提高PDE10A的抑制力和选择性（相对于PDE3A / B）。这些努力最终导致了29种PDE10A的有效和选择性脑可渗透抑制剂的发现。