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

• Published in: Bioorganic & medicinal chemistry letters 2010-12, Vol.20 (23), p.7164-7168
• Main Authors: Wang, Jane L., Aston, Karl, Limburg, David, Ludwig, Cindy, Hallinan, Ann E., Koszyk, Francis, Hamper, Bruce, Brown, David, Graneto, Matthew, Talley, John, Maziasz, Timothy, Masferrer, Jaime, Carter, Jeffery
• Format: Article
• Language: English
• Subjects: Acids; Analgesics; Benzopyran; Benzopyrans - chemistry; Benzopyrans - pharmacokinetics; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carboxylic Acids; Clinical candidate; Cyclooxygenase; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacokinetics; Dose-Response Relationship, Drug; Drug Discovery - methods; Half-Life; Humans; Medical sciences; Metabolism; Microdose; Microsomal; Neuropharmacology; Pharmacology. Drug treatments; Plasma protein bound; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.07.059

Our 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. 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.