The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part III: The three microdose candidates

In this manuscript, we report the discovery of the substituted 2-trifluoromethyl-2H-benzopyran-3-carboxylic acids as a novel series of potent and selective cyclooxygenase-2 (COX-2) inhibitors. We provide the structure–activity relationships, optimization of design, testing criteria, and human half-life data. The challenge of a surprisingly long half-life (t1/2 = 360 h) of the first clinical candidate 1 and human t1/2 had been difficult to predict based on allometric scaling for this class of highly ppb compounds. We used a microdose strategy which led to the discovery of clinical agents 18c-(S), 29b-(S), and 34b-(S) with human half-life of 57, 13, and 11 h.

Graphical abstractOur objective described in this Letter was to discover selective inhibitors of COX-2 that were efficacious in animal models of inflammation and pain and that would exhibit acceptable pharmacokinetic properties allowing them to advance into clinical development, following SC-75416 (2), already in clinical trials.Since incorporation of metabolically labile moieties in this series provided a means for reducing their half-life, in this Letter we discuss the extension of this strategy and the application of a Phase I human microdose screening strategy to advance compounds for which allometric scaling had been marked by a high degree of uncertainty. Using this Phase I microdose screening strategy, we rapidly obtained human pharmacokinetic data for the three clinical agents 18c-(S), 29b-(S), and 34b-(S) affording us the data to allow selection of appropriate candidates for further development.Figure optionsDownload full-size imageDownload as PowerPoint slide