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

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.