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

• DOI: 10.1021/ml500299q
• Publication Date: 2014-07-27T15:51:13Z
• Authors: Yanmei Zhang; Micky D. Tortorella; Yican Wang; Jianqi Liu; Zhengchao Tu; Xiaorong Liu; Yang Bai; Dingsheng Wen; Xin Lu; Yongzhi Lu; John J. Talley
• Keywords: Benzopyrans; Stereoisomerism; Pharmacodynamics; Domino

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