title: Synthesis of Deuterated Benzopyran Derivatives as Selective COX-2 Inhibitors with Improved Pharmacokinetic Properties.
abstract: 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.
authors.affiliation: Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health , Science City, Guangzhou 510530, P. R. China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health , Science City, Guangzhou 510530, P. R. China.
authors.forename: Micky D
authors.initials: MD
authors.lastname: Tortorella
authors.affiliation: Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health , Science City, Guangzhou 510530, P. R. China.
authors.forename: Yican
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health , Science City, Guangzhou 510530, P. R. China.
authors.forename: Jianqi
authors.initials: J
authors.lastname: Liu
authors.affiliation: Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health , Science City, Guangzhou 510530, P. R. China.
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.affiliation: Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health , Science City, Guangzhou 510530, P. R. China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health , Science City, Guangzhou 510530, P. R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health , Science City, Guangzhou 510530, P. R. China.
authors.forename: Dingsheng
authors.initials: D
authors.lastname: Wen
authors.affiliation: Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health , Science City, Guangzhou 510530, P. R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health , Science City, Guangzhou 510530, P. R. China.
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Chemistry, St. Louis University , St. Louis, Missouri 63108, United States ; Euclises Pharmaceuticals, St. Louis, Missouri 63108, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Talley
keywords: COX-2; NSAID; benzopyran; coxib; deuterium