The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part III: The three microdose candidates Jane L. Wang * , Karl Aston, David Limburg, Cindy Ludwig, Ann E. Hallinan, Francis Koszyk, Bruce Hamper, David Brown, Matthew Graneto, John Talley, Timothy Maziasz, Jaime Masferrer, Jeffery Carter Pfizer Global Research and Development, 700 Chesterfield PKWY West, Chesterfield, MO 63017, United States article info Article history: Received 14 January 2010 Revised 12 July 2010 Accepted 14 July 2010 Available online 23 July 2010 Keywords: Cyclooxygenase Clinical candidate Benzopyran Half-life Plasma protein bound Microdose Microsomal Metabolism abstract In this manuscript, we report the discovery of the substituted 2-trifluoromethyl-2H-benzopyran-3-car- boxylic 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. Ó 2010 Elsevier Ltd. All rights reserved. In Part I of this Letter we described the discovery of the substi- tuted 2-trifluoromethyl-2H-benzopyran-3-carboxylic acids as a novel series of potent and selective cyclooxygenase-2 (COX-2) inhibitors. We discussed the discovery of the first clinical candidate 1 (SD-8381) 1 that had excellent potency and efficacy as an analge- sic and anti-inflammatory agent. 1 In Part II of this Letter, we de- scribed the incorporation of metabolically labile moieties to the first clinical candidate 1 to provide a path to shorten its half-life, which led to discovery of second clinical candidate 2 (SC-75416) ( Fig. 1). Compound 2 (SC-75416) also had excellent potency and efficacy as an analgesic and anti-inflammatory agent. It displayed a much shorter human half-life (t 1/2 = 34 h) compared to com- pound 1 (t 1/2 = 360 h), a half-life was appropriate for once-a-day dosing. During our ongoing chemistry program, our goal was to identify potent and selective COX-2 inhibitors as backup candidates of compound 2 (SC-75416) with good PK and metabolism. In both Parts I and II of these Letters, we reported the results of exploration of the 5-position and the 7-position of the benzopyran while keep- ing the 6-choro substituent constant. We also described the explo- ration of the 8-position of the benzopyran that extended into and made contacts within the side-pocket binding region based on celecoxib and compound 1 (SD-8381)’s X-ray structures. These early modifications of substituents about the pyran nucleus showed that the 2-trifluoromethyl, 3-carboxy, and 4-H substitutes were key elements of the pharmacophore, and these compounds 0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.07.059 * Corresponding author. Tel.: +1 636 527 5037; fax: +1 636 247 2086. E-mail address: jl47wang@yahoo.com (J.L. Wang). Figure 1. 1 (SD-8381), a lead COX-2 inhibitor (see Part I of this Letter) and 2 (SC- 75416), a lead COX-2 inhibitor (see Part II of this Letter). (a) See Ref. 2c sec. 2.4 and Ref. 3. (b) See Ref. 2c sec. 2.9. (c and d) See Ref. 2a–c sec. 2.10. (e) See Ref. 2a–c sec. 2.11. Bioorganic & Medicinal Chemistry Letters 20 (2010) 7164–7168 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl