ABSTRACT
Combination of the structure-based design and solid-phase parallel synthesis provided an integrated approach to rapidly develop the structure-activity relationship of benzopyran COX-2 inhibitors. Binding free energies predicted by free energy perturbation theory yielded good agreement with experimental results. New potent and selective lead compounds with improved metabolic properties were identified.
Subject(s)
Benzopyrans/chemistry , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2/chemistry , Microsomes/metabolism , Animals , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Chemistry, Pharmaceutical , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/pharmacology , Humans , Protein Binding , Rats , Structure-Activity Relationship , ThermodynamicsABSTRACT
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 1t(1/2)=360 h was addressed by multiple strategies, leading to the discovery of 29b-(S) (SC-75416) with t(1/2)=34 h.
