American Chemical Society
jm6b01484_si_001.pdf (3.57 MB)

Pentafluorosulfanyl-Substituted Benzopyran Analogues As New Cyclooxygenase‑2 Inhibitors with Excellent Pharmacokinetics and Efficacy in Blocking Inflammation

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journal contribution
posted on 2017-05-05, 17:24 authored by Yanmei Zhang, Yican Wang, Chuang He, Xiaorong Liu, Yongzhi Lu, Tingting Chen, Qiong Pan, Jingfang Xiong, Miaoqin She, Zhengchao Tu, Xiaochu Qin, Minke Li, Micky D. Tortorella, John J. Talley
In this report, we disclose the design and synthesis of a series of pentafluorosulfanyl (SF5) benzopyran derivatives as novel COX-2 inhibitors with improved pharmacokinetic and pharmacodynamic properties. The pentafluorosulfanyl compounds showed both potency and selectivity for COX-2 and demonstrated efficacy in several murine models of inflammation and pain. More interestingly, one of the compounds, R,S-3a, revealed exceptional efficacy in the adjuvant induced arthritis (AIA) model, achieving an ED50 as low as 0.094 mg/kg. In addition, the pharmacokinetics of compound R,S-3a in rat revealed a half-life in excess of 12 h and plasma drug concentrations well above its IC90 for up to 40 h. When R,S-3a was dosed just two times a week in the AIA model, efficacy was still maintained. Overall, drug R,S-3a and other analogues are suitable candidates that merit further investigation for the treatment of inflammation and pain as well as other diseases where COX-2 and PGE2 play a role in their etiology.