The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part III: the three microdose candidates.
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.
Wang
Jane L
JL
Pfizer Global Research and Development, Chesterfield, MO 63017, USA. jl47wang@yahoo.com
Aston
Karl
K
Limburg
David
D
Ludwig
Cindy
C
Hallinan
Ann E
AE
Koszyk
Francis
F
Hamper
Bruce
B
Brown
David
D
Graneto
Matthew
M
Talley
John
J
Maziasz
Timothy
T
Masferrer
Jaime
J
Carter
Jeffery
J
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
D001578:Benzopyrans; D002264:Carboxylic Acids; D052246:Cyclooxygenase 2 Inhibitors