title: Substrate-Selective Inhibition of Cyclooxygenase-2: Development and Evaluation of Achiral Profen Probes.
abstract: Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid and the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA). We recently reported that (R)-profens selectively inhibit endocannabinoid oxygenation but not arachidonic acid oxygenation. In this work, we synthesized achiral derivatives of five profen scaffolds and evaluated them for substrate-selective inhibition using in vitro and cellular assays. The size of the substituents dictated the inhibitory strength of the analogs, with smaller substituents enabling greater potency but less selectivity. Inhibitors based on the flurbiprofen scaffold possessed the greatest potency and selectivity, with desmethylflurbiprofen (3a) exhibiting an IC(50) of 0.11 μM for inhibition of 2-AG oxygenation. The crystal structure of desmethylflurbiprofen complexed to mCOX-2 demonstrated a similar binding mode to other profens. Desmethylflurbiprofen exhibited a half-life in mice comparable to that of ibuprofen. The data presented suggest that achiral profens can act as lead molecules toward in vivo probes of substrate-selective COX-2 inhibition.
authors.affiliation: A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry, and Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, and Vanderbilt-Ingram Cancer Center,  Vanderbilt University School of Medicine , Nashville, Tennessee, United States.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Windsor
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hermanson
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kingsley
authors.forename: Shu
authors.initials: S
authors.lastname: Xu
authors.forename: Brenda C
authors.initials: BC
authors.lastname: Crews
authors.forename: Winnie
authors.initials: W
authors.lastname: Ho
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Keenan
authors.forename: Surajit
authors.initials: S
authors.lastname: Banerjee
authors.forename: Keith A
authors.initials: KA
authors.lastname: Sharkey
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett