Synthesis and in?vitro evaluation of new analogues as inhibitors for phosphodiesterase 10A

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• 作者：Zhanbin Zhang¹ ; Xiaoxia Lu ; Jinbin Xu ; Justin Rothfuss ; Robert H. Mach ; Zhude Tu ; ^{tuz@mir.wustl.edu}
• 关键词：PDE10A ; CNS ; Schizophrenia
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：September, 2011
• 年：2011
• 卷：46
• 期：9
• 页码：3986-3995
• 全文大小：647 K

文摘

A series of analogues were synthesized by optimizing the structure of papaverine. The in?vitro PDE10A binding affinity (IC₅₀) values for these new analogues were measured; for compounds that have IC₅₀ value less than 60?nM for PDE10A, the binding affinities (IC₅₀ value) for PDE3A and PDE3B were tested. Of?these analogues, compounds 6a, 6b, 6n, 8b, 8c and 11 displayed relatively higher PDE10A potency with IC₅₀ value in the range of 28-60?nM. The most potent compound 1-(4-(2-(2-fluoroethoxy)ethoxy)-3-methoxybenzyl)-6,7-dimethoxyisoquinoline (8c) has the IC₅₀ value of 28?¡À?1.2?nM for PDE10A, 2200?¡À?437?nM for PDE3A and 2520?¡À?210?nM for PDE3B. Compared to papaverine, compound 8c displayed similar PDE10A potency but improved selectivity to PDE10A versus PDE3A and PDE3B. To?identify high potent PDE10A inhibitor, further optimization of the structures of these analogues is necessary.