一系列6,7-二甲氧基-4-吡咯烷基喹唑啉磷酸二酯酶10A抑制剂的发现。
Discovery of a series of 6,7-dimethoxy-4-pyrrolidylquinazoline PDE10A inhibitors.
作者信息
Chappie Thomas A, Humphrey John M, Allen Martin P, Estep Kimberly G, Fox Carol B, Lebel Lorraine A, Liras Spiros, Marr Eric S, Menniti Frank S, Pandit Jayvardhan, Schmidt Christopher J, Tu Meihua, Williams Robert D, Yang Feng V
机构信息
CNS Discovery and Experimental Medicinal Sciences, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA.
出版信息
J Med Chem. 2007 Jan 25;50(2):182-5. doi: 10.1021/jm060653b.
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.
通过基于结构的药物设计（SBDD）生成了一种用于抑制磷酸二酯酶10A（PDE10A）的基于罂粟碱的药效团模型，并用于设计4-氨基-6,7-二甲氧基喹唑啉文库。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，该系列成为进一步建模、X射线研究以及提高PDE10A抑制效力和相对于磷酸二酯酶3A/B（PDE3A/B）的选择性的合成努力的重点。这些努力最终发现了化合物29，一种强效且具有选择性的可穿透脑屏障的PDE10A抑制剂。
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