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

Abstract In this manuscript, we report the discovery of the substituted 2-trifluoromethyl-2 H -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 ( t 1/2  = 360 h) of the first clinical candidate 1 and human t 1/2 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.