title: Distinction of microsomal prostaglandin E synthase-1 (mPGES-1) inhibition from cyclooxygenase-2 inhibition in cells using a novel, selective mPGES-1 inhibitor.
abstract: Inflammation-induced microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme that synthesizes prostaglandin E(2) (PGE(2)) downstream of cyclooxygenase-2 (COX-2). The efficacy of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors in the treatment of the signs and symptoms of osteoarthritis, rheumatoid arthritis and inflammatory pain, largely attributed to the inhibition of PGE(2) synthesis, provides a rationale for exploring mPGES-1 inhibition as a potential novel therapy for these diseases. Toward this aim, we identified PF-9184 as a novel mPGES-1 inhibitor. PF-9184 potently inhibited recombinant human (rh) mPGES-1 (IC(50)=16.5+/-3.8nM), and had no effect against rhCOX-1 and rhCOX-2 (>6500-fold selectivity). In inflammation and clinically relevant biological systems, mPGES-1 expression, like COX-2 expression was induced in cell context- and time-dependent manner, consistent with the kinetics of PGE(2) synthesis. In rationally designed cell systems ideal for determining direct effects of the inhibitors on mPGES-1 function, but not its expression, PF-9184 inhibited PGE(2) synthesis (IC(50) in the range of 0.5-5 microM in serum-free cell and human whole blood cultures, respectively) while sparing the synthesis of 6-keto-PGF(1alpha) (PGF(1alpha)) and PGF(2alpha). In contrast, as expected, the selective COX-2 inhibitor, SC-236, inhibited PGE(2), PGF(1alpha) and PGF(2alpha) synthesis. This profile of mPGES-1 inhibition, distinct from COX-2 inhibition in cells, validates mPGES-1 as an attractive target for therapeutic intervention.
authors.affiliation: Pfizer Inc., Chesterfield, MO 63017, USA. gabriel.mbalaviele@pfizer.com
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mbalaviele
authors.forename: Adele M
authors.initials: AM
authors.lastname: Pauley
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Shaffer
authors.forename: Ben S
authors.initials: BS
authors.lastname: Zweifel
authors.forename: Sumathy
authors.initials: S
authors.lastname: Mathialagan
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Mnich
authors.forename: Olga V
authors.initials: OV
authors.lastname: Nemirovskiy
authors.forename: Jeff
authors.initials: J
authors.lastname: Carter
authors.forename: James K
authors.initials: JK
authors.lastname: Gierse
authors.forename: Jane L
authors.initials: JL
authors.lastname: Wang
authors.forename: Michael L
authors.initials: ML
authors.lastname: Vazquez
authors.forename: William M
authors.initials: WM
authors.lastname: Moore
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Masferrer
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D002351:Carrageenan / Q000494:pharmacology; D002478:Cells, Cultured; D003499:Cyclic S-Oxides / Q000037:antagonists & inhibitors*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D053583:Interleukin-1beta / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D000071876:Prostaglandin-E Synthases; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013843:Thiazines / Q000037:antagonists & inhibitors*
chemical_list: D003499:Cyclic S-Oxides; D052246:Cyclooxygenase 2 Inhibitors; D053583:Interleukin-1beta; C548452:N-(3',4'-dichlorobiphenyl-4-yl)-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide; D013843:Thiazines; D002351:Carrageenan; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases