title: The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: the second clinical candidate having a shorter and favorable human half-life.
abstract: 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.
authors: Pfizer Global Research and Development, Chesterfield, MO 63017, USA. jl47wang@yahoo.com
authors: Jane L
authors: JL
authors: Wang
authors: David
authors: D
authors: Limburg
authors: Matthew J
authors: MJ
authors: Graneto
authors: John
authors: J
authors: Springer
authors: Joseph Rogier Bruce
authors: JR
authors: Hamper
authors: Subo
authors: S
authors: Liao
authors: Jennifer L
authors: JL
authors: Pawlitz
authors: Ravi G
authors: RG
authors: Kurumbail
authors: Timothy
authors: T
authors: Maziasz
authors: John J
authors: JJ
authors: Talley
authors: James R
authors: JR
authors: Kiefer
authors: Jeffery
authors: J
authors: Carter
mesh_terms: D001578:Benzopyrans / Q000737:chemistry* / Q000493:pharmacokinetics*; D001665:Binding Sites; D020134:Catalytic Domain; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D001578:Benzopyrans; D052246:Cyclooxygenase 2 Inhibitors