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Bioorg Med Chem Lett. 2010 Dec 1;20(23):7164-8. doi: 10.1016/j.bmcl.2010.07.059. Epub 2010 Jul 23.

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

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Pfizer Global Research and Development, Chesterfield, MO 63017, USA.


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 (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.

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