The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: the second clinical candidate having a shorter and favorable human half-life.
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.
Wang
Jane L
JL
Pfizer Global Research and Development, Chesterfield, MO 63017, USA. jl47wang@yahoo.com
Limburg
David
D
Graneto
Matthew J
MJ
Springer
John
J
Hamper
Joseph Rogier Bruce
JR
Liao
Subo
S
Pawlitz
Jennifer L
JL
Kurumbail
Ravi G
RG
Maziasz
Timothy
T
Talley
John J
JJ
Kiefer
James R
JR
Carter
Jeffery
J
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
D001578:Benzopyrans; D052246:Cyclooxygenase 2 Inhibitors