Details

Autor(en) / Beteiligte

• Zhang, Yanmei
• Wang, Yican
• He, Chuang
• Liu, Xiaorong
• Lu, Yongzhi
• Chen, Tingting
• Pan, Qiong
• Xiong, Jingfang
• She, Miaoqin
• Tu, Zhengchao
• Qin, Xiaochu
• Li, Minke
• Tortorella, Micky D
• Talley, John J

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2017-05, Vol.60 (10), p.4135-4146

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.