Effects of AF3442 [N-(9-ethyl-9H-carbazol-3-yl)-2-(trifluoromethyl)benzamide], a novel inhibitor of human microsomal prostaglandin E synthase-1, on prostanoid biosynthesis in human monocytes in vitro

Biochemical Pharmacology
Annalisa BrunoPaola Patrignani

Abstract

Inhibitors of microsomal prostaglandin (PG) E synthase-1 (mPGES-1) are being developed for the relief of pain. Redirection of the PGH(2) substrate to other PG synthases, found both in vitro and in vivo, in mPGES-1 knockout mice, may influence their efficacy and safety. We characterized the contribution of mPGES-1 to PGH(2) metabolism in lipopolysaccharide (LPS)-stimulated isolated human monocytes and whole blood by studying the synthesis of prostanoids [PGE(2), thromboxane (TX)B(2), PGF(2alpha) and 6-keto-PGF(1alpha)] and expression of cyclooxygenase (COX)-isozymes and down-stream synthases in the presence of pharmacological inhibition by the novel mPGES-1 inhibitor AF3442 [N-(9-ethyl-9H-carbazol-3-yl)-2-(trifluoromethyl)benzamide]. AF3442 caused a concentration-dependent inhibition of PGE(2) in human recombinant mPGES-1 with an IC(50) of 0.06microM. In LPS-stimulated monocytes, AF3442 caused a concentration-dependent reduction of PGE(2) biosynthesis with an IC(50) of 0.41microM. At 1microM, AF3442 caused maximal selective inhibitory effect of PGE(2) biosynthesis by 61+/-3.3% (mean+/-SEM, P<0.01 versus DMSO vehicle) without significantly affecting other prostanoids (i.e. TXB(2), PGF(2alpha) and 6-keto-PGF(1alpha)). In LPS-stimu...Continue Reading

References

Jun 1, 1982·The Journal of Clinical Investigation·P PatrignaniC Patrono
Jun 23, 1999·Proceedings of the National Academy of Sciences of the United States of America·P J JakobssonB Samuelsson
Jun 22, 2001·The Journal of Biological Chemistry·N UenoI Kudo
Jul 4, 2001·The Journal of Clinical Investigation·C PatronoL A García Rodríguez
Jan 5, 2002·The New England Journal of Medicine·C M Nzerue
Feb 25, 2003·British Journal of Pharmacology·Maria G SciulliPaola Patrignani
Jun 15, 2005·Bioorganic & Medicinal Chemistry Letters·Denis RiendeauRichard W Friesen
Sep 6, 2005·Biochemical and Biophysical Research Communications·Noriko UenoMakoto Murakami
Mar 17, 2006·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Jean Y ParkSteven B Abramson
Sep 16, 2006·Proceedings of the National Academy of Sciences of the United States of America·Miao WangGarret A FitzGerald
Dec 14, 2006·Prostaglandins & Other Lipid Mediators·Marta L CaponePaola Patrignani
Apr 16, 2008·Journal of Internal Medicine·M WangG A Fitzgerald
Jun 19, 2008·Experimental Dermatology·Claudia SkazikJens Malte Baron
Nov 11, 2008·Journal of the American College of Cardiology·Luis Alberto García RodríguezPaola Patrignani

❮ Previous
Next ❯

Citations

Sep 21, 2013·Prostaglandins & Other Lipid Mediators·Patrick LeclercPer-Johan Jakobsson
Aug 7, 2013·Expert Reviews in Molecular Medicine·Tülay Yucel-Lindberg, Tove Båge
Mar 1, 2013·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Anna KatsTülay Yucel-Lindberg
Aug 2, 2011·Biological & Pharmaceutical Bulletin·Atsufumi Kawabata
Oct 26, 2011·Future Medicinal Chemistry·Hui-Hua Chang, Emmanuelle J Meuillet
Feb 7, 2012·Inflammation and Regeneration·Fumiaki KojimaLeslie J Crofford
Apr 30, 2013·Prostaglandins & Other Lipid Mediators·Louise R HoweAndrew J Dannenberg
Mar 27, 2013·Prostaglandins & Other Lipid Mediators·Patrick LeclercPer-Johan Jakobsson
Mar 20, 2012·Trends in Molecular Medicine·M Dolores SalvadoJuan Miguel Redondo
Oct 22, 2013·Basic & Clinical Pharmacology & Toxicology·Marina Korotkova, Per-Johan Jakobsson
Jul 30, 2011·The Biochemical Journal·Shan HeLuhua Lai
Dec 23, 2016·Medicinal Research Reviews·Catarina Pereira-LeiteSalette Reis
Jul 16, 2014·Medicinal Research Reviews·Malkeet Singh BahiaPragati Silakari
Jan 16, 2021·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·Anna-Karin JohnssonGunnar Nilsson
Feb 13, 2021·Scientific Reports·Shuo ZhouChang-Guo Zhan
Jul 12, 2017·Bioorganic & Medicinal Chemistry Letters·Ziyuan ZhouChang-Guo Zhan

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.