Pentafluorosulfanyl-Substituted Benzopyran Analogues As New Cyclooxygenase-2 Inhibitors with Excellent Pharmacokinetics and Efficacy in Blocking Inflammation.
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| Abstract |
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.
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| Authors | 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 |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 60 Issue 10 Pg. 4135-4146 (05 25 2017) ISSN: 1520-4804 [Electronic] United States |
| PMID | 28475316 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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