Abstract
We present the in vitro characterization of a novel phosphodiesterase type 4 inhibitor, CDP840 (R-[+]-4-[2-¿3-cyclopentyloxy-4-methoxyphenyl¿-2-phenylethyl]pyridine), which has shown efficacy in a phase II allergen challenge study in asthmatics without adverse effects. CDP840 potently inhibits PDE-4 isoenzymes (IC50 2-30 nM) without any effect on PDE-1, 2, 3, 5, and 7 (IC50 > 100 microM). It exhibited no significant selectivity in inhibiting human recombinant isoenzymes PDE-4A, B, C or D and was equally active against the isoenzymes lacking UCR1 (PDE-4B2 and PDE-4D2). In contrast to rolipram, CDP840 acted as a simple competitive inhibitor of all PDE-4 isoenzymes. Studies with rolipram indicated a heterogeneity within all the preparations of PDE-4 isoenzymes, indicative of rolipram inhibiting the catalytic activity of PDE-4 with both a low or high affinity. These observations were confirmed by the use of a PDE-4A variant, PDE-4A330-886, which rolipram inhibited with low affinity (IC50 = 1022 nM). CDP840 in contrast inhibited this PDE-4A variant with similar potency (IC50 = 3.9 nM), which was in good agreement with the Kd of 4.8 nM obtained from [3H]-CDP840 binding studies. Both CDP840 and rolipram inhibited the high-affinity bin...Continue Reading
References
Oct 15, 1992·Biological Psychiatry·B SaletuF Böhmer
Jul 1, 1991·Thorax·T J Torphy, B J Undem
Jan 1, 1990·Psychopharmacology·R SchmiechenH Wachtel
Jul 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·J V SwinnenM Conti
Jul 1, 1989·Pharmacopsychiatry·G F HebenstreitW Soukop
Aug 7, 1986·European Journal of Pharmacology·H H SchneiderJ Seidler
Dec 1, 1994·The Biochemical Journal·M WilsonM D Houslay
May 1, 1995·British Journal of Pharmacology·J E SounessJ A Karlsson
Nov 1, 1994·Cellular Signalling·G B Bolger
Oct 1, 1993·Analytical Biochemistry·B J SmithM J Perry
Oct 1, 1993·Molecular and Cellular Biology·G BolgerK Ferguson
Apr 12, 1996·Biochemical Pharmacology·M S BarnetteT J Torphy
Jul 12, 1996·The Journal of Biological Chemistry·C Sette, M Conti
Aug 15, 1996·The Biochemical Journal·J C O'ConnellM D Houslay
Jun 1, 1996·British Journal of Pharmacology·J E SounessJ A Karlsson
Jan 1, 1996·Progress in Medicinal Chemistry·M N Palfreyman, J E Souness
Jul 1, 1996·British Journal of Pharmacology·B HughesG Higgs
Jul 1, 1996·British Journal of Pharmacology·M HolbrookB Hughes
Jul 1, 1996·British Journal of Pharmacology·N GozzardC P Page
Dec 6, 1996·The Journal of Biological Chemistry·E HustonM D Houslay
Mar 11, 1997·Biochemistry·T KovalaE H Ball
May 1, 1997·The European Respiratory Journal·P L HarbinsonT H Lee
Aug 15, 1997·The Biochemical Journal·R J OwensM J Perry
Jan 16, 1998·Cellular Signalling·R J OwensM J Perry
Aug 1, 1953·The Biochemical Journal·M DIXON
Citations
Jun 19, 1998·Cell Biochemistry and Biophysics·D J PonI W Rodger
Jun 3, 1999·Biochemical Pharmacology·R A AllenR J Owens
Jun 18, 1999·British Journal of Pharmacology·N CooperP G Hellewell
Mar 2, 2006·Toxicologic Pathology·Gregory N DietschSuzanne T Kanaly
Jun 7, 2014·Frontiers in Neuroscience·Yuri A BlednovR Adron Harris
Aug 17, 2005·Pharmacology & Therapeutics·Claire Lugnier
Feb 20, 2002·FEBS Letters·France LalibertéZheng Huang
Dec 7, 2018·Angewandte Chemie·Belén RubialVarinder K Aggarwal
Sep 4, 2009·Journal of Biomechanical Engineering·David M PierceGerhard A Holzapfel
Nov 17, 2009·Annals of Biomedical Engineering·Susan M MooreRichard E Debski
Mar 3, 2018·Nature Communications·B WeberD Bonn
Aug 29, 2003·Nature·Alexander I CulleyCurtis A Suttle
Aug 7, 2007·Journal of Enzyme Inhibition and Medicinal Chemistry·Maria P GiovannoniVittorio Dal Piaz
Jun 6, 2008·Journal of Biomechanical Engineering·Arturo N NataliMartin Geiger
Mar 24, 2000·Drugs·M A Giembycz
Jan 12, 2020·Pharmacology & Therapeutics·Claire LugnierBernard Geny
Oct 29, 2000·Journal of Medicinal Chemistry·D MacdonaldZ Huang
Sep 16, 1998·Current Opinion in Chemical Biology·M J Perry, G A Higgs