In vitro pharmacology of the novel phosphodiesterase type 4 inhibitor, CP-80633.

Abstract

We present the in vitro pharmacology of a novel adenosine 3'-5' -cyclic monophosphate-specific phosphodiesterase (PDE) type 4 inhibitor, CP-80633 ((2'S)5-[3-(2' -exobicyclo[2.2.1]-heptyloxy)4-methoxyphenyl] tetrahydro-2(1H)-primidone), which has shown efficacy in phase II clinical trials for atopic dermatitis. CP-80633 inhibits PDE4 isozymes (human lung IC50 = 1.27 microM) in the absence of effects on PDE1, PDE2, PDE3 and PDE5 isozymes (IC50 > 100 microM). It exhibits no significant selectivity for any single cloned PDE4A, B, C or D isoform. CP-80633 inhibits adenosine 3'-5'-cyclic monophosphate hydrolysis in partially purified human peripheral blood monocyte cytosol (IC50 = 3.52 microM), eosinophil membrane (IC50 = 1.10 microM) and T cell membrane (IC50 = 2.28 microM) preparations. Inhibition of eosinophil PDE4 adenosine 3'-5'-cyclic mono-phosphate hydrolysis by CP-80,633 occurs in a noncompetitive manner. Unlike theophylline, CP-80,633 is inactive against ratrain adenosine (A1,A2) receptors. Consistent with its action as a PDE4 inhibitor in whole cells, CP-80633 potentiates PGE1 dependent increases in adenosine 3'-5'-cyclic monophosphate levels in human U937 cells, and in human eosinophils, monocytes and T cells (EC200 approximately 1.0 microM). Consequently, CP-80633 inhibits many inflammatory cell functions including 1) human eosinophil superoxide anion production (IC50 < 0.6 microM), 2 C5a-(IC50 = 0.40 microM) and LTB4-(IC50 = 0.20 microM) mediated guinea pig peritoneal eosinophil chemotaxis and 3) lipopolysac-charide-induced tumor necrosis factor-alpha release from human monocytes (IC50 = 0.219 microM). These data clearly demonstrate that CP-80633 is a selective inhibitor of PDE4 isozymes, and support its potential use as a therapeutic agent for a number of inflammatory and immune disorders.

• Authors: V L Cohan, H J Showell, D A Fisher, C J Pazoles, J W Watson, C R Turner, J B Cheng
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 278 Issue 3 Pg. 1356-61 (Sep 1996) ISSN: 0022-3565 [Print] United States
• PMID: 8819523 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Bronchodilator Agents
• CP 80633
• Isoenzymes
• Phosphodiesterase Inhibitors
• Pyrimidinones
• Pyrrolidinones
• Receptors, Purinergic P1
• Superoxides
• Theophylline
• Cyclic AMP
• Phosphoric Diester Hydrolases
• 3',5'-Cyclic-AMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 1
• Cyclic Nucleotide Phosphodiesterases, Type 4
• PDE4A protein, human
• Rolipram

Topics

• 3',5'-Cyclic-AMP Phosphodiesterases
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Binding, Competitive
• Bronchodilator Agents (pharmacology)
• Cloning, Molecular
• Cyclic AMP (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 1
• Cyclic Nucleotide Phosphodiesterases, Type 4
• Eosinophils (drug effects)
• Guinea Pigs
• Humans
• Isoenzymes (antagonists & inhibitors)
• Kinetics
• Monocytes (drug effects)
• Phosphodiesterase Inhibitors (pharmacology)
• Phosphoric Diester Hydrolases
• Pyrimidinones (pharmacology)
• Pyrrolidinones (pharmacology)
• Rats
• Receptors, Purinergic P1 (drug effects)
• Rolipram
• Substrate Specificity
• Superoxides (metabolism)
• Theophylline (pharmacology)