CDP840: a novel inhibitor of PDE-4

Cell Biochemistry and Biophysics
M PerryR J Owens

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

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Citations

Jun 7, 2014·Frontiers in Neuroscience·Yuri A BlednovR Adron Harris
Feb 20, 2002·FEBS Letters·France LalibertéZheng Huang
Nov 17, 2009·Annals of Biomedical Engineering·Susan M MooreRichard E Debski
Aug 29, 2003·Nature·Alexander I CulleyCurtis A Suttle
Aug 7, 2007·Journal of Enzyme Inhibition and Medicinal Chemistry·Maria P GiovannoniVittorio Dal Piaz
Jan 12, 2020·Pharmacology & Therapeutics·Claire LugnierBernard Geny
Sep 16, 1998·Current Opinion in Chemical Biology·M J Perry, G A Higgs

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