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

Journal Article · Tue May 29 00:00:00 EDT 2012 · Bioorg. Med. Chem. Lett.

DOI:https://doi.org/10.1016/j.bmcl.2010.07.054· OSTI ID:1025630

Wang, Jane L; Limburg, David; Graneto, Matthew J; Springer, John; Hamper, Joseph Rogier Bruce; Liao, Subo; Pawlitz, Jennifer L; Kurumbail, Ravi G; Maziasz, Timothy; Talley, John J; Kiefer, James R; Carter, Jeffery ^[1]

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1. Pfizer

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{sub 1/2} = 360 h was addressed by multiple strategies, leading to the discovery of 29b-(S) (SC-75416) with t{sub 1/2} = 34 h.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: INDUSTRY
• OSTI ID: 1025630
• Journal Information: Bioorg. Med. Chem. Lett., Journal Name: Bioorg. Med. Chem. Lett. Journal Issue: (23) ; 12, 2010 Vol. 20
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
CRYSTAL STRUCTURE
DESIGN
HALF-LIFE
OPTIMIZATION
PLASMA
PROTEINS
STRUCTURE-ACTIVITY RELATIONSHIPS
TESTING