title: The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part III: the three microdose candidates.
abstract: In this manuscript, we report the discovery of the substituted 2-trifluoromethyl-2H-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.
authors: Pfizer Global Research and Development, Chesterfield, MO 63017, USA. jl47wang@yahoo.com
authors: Jane L
authors: JL
authors: Wang
authors: Karl
authors: K
authors: Aston
authors: David
authors: D
authors: Limburg
authors: Cindy
authors: C
authors: Ludwig
authors: Ann E
authors: AE
authors: Hallinan
authors: Francis
authors: F
authors: Koszyk
authors: Bruce
authors: B
authors: Hamper
authors: David
authors: D
authors: Brown
authors: Matthew
authors: M
authors: Graneto
authors: John
authors: J
authors: Talley
authors: Timothy
authors: T
authors: Maziasz
authors: Jaime
authors: J
authors: Masferrer
authors: Jeffery
authors: J
authors: Carter
mesh_terms: D001578:Benzopyrans / Q000737:chemistry / Q000493:pharmacokinetics*; D002264:Carboxylic Acids; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D006207:Half-Life; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D001578:Benzopyrans; D002264:Carboxylic Acids; D052246:Cyclooxygenase 2 Inhibitors