The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: The second clinical candidate having a shorter and favorable human half-life

In this Letter, we provide the structure–activity relationships, optimization of design, testing criteria, and human half-life data for a series of selective COX-2 inhibitors. During the course of our structure-based drug design efforts, we discovered two distinct binding modes within the COX-2 active site for differently substituted members of this class. The challenge of a undesirably long human half-life for the first clinical candidate 1t1/2 = 360 h was addressed by multiple strategies, leading to the discovery of 29b-(S) (SC-75416) with t1/2 = 34 h.

We describe our strategy to discover a selective inhibitor of COX-2 with a shorter human half-life compared with the previous clinical candidate SD-8381 (5c-(S), t1/2 ∼160 h). In this paper, we disclose a series of selective COX-2 inhibitors based on the benzopyran template that display potency against COX-2 in animal models of pain and inflammation. We also discussed the discovery of two COX-2 binding modes and utilizing the microsomal data as a filter leading to the discovery of clinical candidate 29b-(S) (SC-75416), successfully advanced through a phase II efficacy trial.Figure optionsDownload as PowerPoint slide