Synthesis of Deuterated Benzopyran Derivatives as Selective COX-2 Inhibitors with Improved Pharmacokinetic Properties

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• 作者：Yanmei Zhang ; Micky D. Tortorella ; Yican Wang ; Jianqi Liu ; Zhengchao Tu ; Xiaorong Liu ; Yang Bai ; Dingsheng Wen ; Xin Lu ; Yongzhi Lu ; John J. Talley
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：October 9, 2014
• 年：2014
• 卷：5
• 期：10
• 页码：1162-1166
• 全文大小：269K
• ISSN：1948-5875

文摘

We designed a series of specifically deuterated benzopyran analogues as new COX-2 inhibitors with the aim of improving their pharmacokinetic properties. As expected, the deuterated compounds retained potency and selectivity for COX-2. The new molecules possess improved pharmacokinetic profiles in rats compared to their nondeuterated congeners. Most importantly, the new compounds showed pharmacodynamic efficacy in several murine models of inflammation and pain. The benzopyran derivatives were separated into their enantiomers, and the activity was found to reside with the S-isomers. To streamline the synthesis of the desired S-isomers, an organocatalytic asymmetric domino oxa-Michael/aldol condensation reaction was developed for their preparation.

Keywords:

COX-2; coxib; deuterium; benzopyran; NSAID