Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a selective inhibitor of phosphodiesterase 7: in vitro studies in human monocytes, lung macrophages, and CD8+ T-lymphocytes

Molecular Pharmacology
Susan J SmithM A Giembycz

Abstract

The biochemical and pharmacological characteristics in human proinflammatory cells of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a novel and selective inhibitor of phosphodiesterase (PDE) 7, are described. BRL 50481 inhibited the activity of hrPDE7A1 expressed in baculovirus-infected Spodoptera frugiperda 9 cells in a competitive manner (Ki value of 180 nM) and was 416 and 1884 times less potent against PDE3 and 38 and 238 times less potent against PDE4 at a substrate concentration of 1 microM and 50 nM cAMP, respectively. Western blotting identified HSPDE7A1 but not HSPDE7A2 in three human cell types that are implicated in the pathogenesis of chronic obstructive lung disease, namely, CD8+ T-lymphocytes, monocytes, and lung macrophages. BRL 50481 had no effect on the proliferation of CD8+ T-lymphocytes and only marginally (approximately 2-11%) reduced the generation of tumor necrosis factor (TNF)alpha from blood monocytes and lung macrophages. However, in the presence of BRL 50481 the inhibitory effect of rolipram was enhanced on all three cell types. The expression of HSPDE7A1 was increased in a time-dependent manner in monocytes that were "aged" in culture medium. Under this condition, BRL 50481 now inhibi...Continue Reading

References

Jul 25, 1991·Biochemical Pharmacology·S A RobicsekJ B Polson
Aug 1, 1988·Cellular Immunology·L E AverillG M Kammer
Nov 26, 1996·Proceedings of the National Academy of Sciences of the United States of America·T J Bloom, J A Beavo
Feb 26, 1998·American Journal of Respiratory and Critical Care Medicine·T J Torphy
Oct 3, 1999·Progress in Nucleic Acid Research and Molecular Biology·M Conti, S L Jin
Jan 5, 2000·Proceedings of the National Academy of Sciences of the United States of America·J M HetmanJ A Beavo
May 18, 2000·Biochemical and Biophysical Research Communications·T SasakiK Omori
Jun 29, 2000·Biochemical and Biophysical Research Communications·C GardnerM Fidock
May 1, 2001·Bioorganic & Medicinal Chemistry Letters·M J BarnesR J Watson
May 24, 2001·Proceedings of the National Academy of Sciences of the United States of America·N A GlavasJ A Beavo
Aug 8, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·K J StaplesR Newton
Sep 17, 2002·European Journal of Biochemistry·Naoko TakahashiTakashi Okamoto
May 10, 2003·The Biochemical Journal·Mònica Torras-Llort, Fernando Azorín
Jun 21, 2003·American Journal of Respiratory and Critical Care Medicine·Elizabeth GamblePeter K Jeffery
Dec 10, 2003·The Journal of Immunology : Official Journal of the American Association of Immunologists·Guchen YangAndrew J Watson
May 6, 2004·Bioorganic & Medicinal Chemistry Letters·William J PittsJoel C Barrish
Aug 25, 2004·Bioorganic & Medicinal Chemistry Letters·Edwige LorthioisPatrick Berna

❮ Previous
Next ❯

Citations

Oct 24, 2007·Applied Microbiology and Biotechnology·Renu MalikKulvinder Singh Saini
Dec 30, 2011·Journal of Medicinal Chemistry·Terence B BeghynBenoit Deprez
Aug 27, 2013·Nature Reviews. Drug Discovery·Peter J Barnes
Nov 27, 2008·Proceedings of the National Academy of Sciences of the United States of America·Lingzhi ZhangPaul A Insel
Oct 22, 2009·American Journal of Respiratory Cell and Molecular Biology·Tricia K Finney-HaywardLouise E Donnelly
Mar 17, 2010·Journal of Biomolecular Screening·Manal A AlaameryCharles S Hoffman
Dec 1, 2007·International Journal of Chronic Obstructive Pulmonary Disease·Girolamo PelaiaSerafino A Marsico
Sep 29, 2011·Future Medicinal Chemistry·Nicolay FerrariPaolo Renzi
Apr 2, 2014·Nature Reviews. Drug Discovery·Donald H MauriceVincent C Manganiello
May 1, 2007·Expert Review of Clinical Immunology·Radhakrishnan Venkatasamy, Domenico Spina
May 29, 2014·Expert Opinion on Investigational Drugs·Maria Gabriella MateraMario Cazzola
Apr 11, 2013·Expert Opinion on Drug Discovery·Maliheh SafaviMohammad Abdollahi
Oct 10, 2007·Expert Opinion on Investigational Drugs·Lalitha VijayakrishnanAbhijit Ray
Mar 7, 2009·Expert Opinion on Emerging Drugs·Carola Seifart, Claus Vogelmeier
Aug 17, 2014·FEBS Letters·Maike MonzelErich H Schneider
Oct 25, 2011·Current Opinion in Pharmacology·Claire Lugnier
Dec 3, 2015·Pharmacology & Therapeutics·Thomas HankeManfred Schubert-Zsilavecz
Nov 11, 2008·International Immunopharmacology·Kumiko Kadoshima-YamaokaTakashi Nishimura
Jun 13, 2008·Protein Expression and Purification·Ranjana AryaKulvinder Singh Saini
Jan 26, 2007·European Journal of Pharmacology·Satoshi YamamotoYasuaki Shimizu
Jul 29, 2008·British Journal of Pharmacology·D Spina
Jul 11, 2012·Journal of Neurochemistry·Cristina SusínAna Perez-Castillo
Jul 23, 2013·British Journal of Pharmacology·C González-GarcíaS Ballester
Sep 4, 2015·Nuclear Medicine and Biology·David ThomaeSteven Staelens
Feb 7, 2006·European Journal of Pharmacology·Kian Fan Chung
Jan 24, 2006·Pulmonary Pharmacology & Therapeutics·N A JonesC P Page
Apr 3, 2016·Glia·Damien D Pearse, Zoë A Hughes
Apr 23, 2014·Fundamental & Clinical Pharmacology·Carolina OteroJuan E Jung
Nov 23, 2005·Expert Opinion on Therapeutic Targets·Kam Y J ZhangGideon Bollag
Jan 13, 2015·Molecular and Cellular Endocrinology·T S PetersenC Y Andersen
Jun 16, 2016·International Immunopharmacology·Chenjia XuThomas C Chiles
May 5, 2004·Pulmonary Pharmacology & Therapeutics·K J RickardsF M Cunningham

❮ 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.