ABSTRACT
The synthesis of a novel series of guanine analogues is reported. The compounds have been assessed in vitro and some analogues have been found to be inhibitors of phosphodiesterase type 7 (PDE7).
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Guanine/chemical synthesis , Guanine/pharmacology , Isoenzymes/antagonists & inhibitors , Cyclic Nucleotide Phosphodiesterases, Type 3 , Cyclic Nucleotide Phosphodiesterases, Type 4 , Cyclic Nucleotide Phosphodiesterases, Type 7 , Enzyme Inhibitors/metabolism , Guanine/analogs & derivatives , Inhibitory Concentration 50 , Structure-Activity RelationshipABSTRACT
The synthesis and pharmacological profile of a novel series of 7-methoxybenzofuran-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Benzofurans/chemical synthesis , Benzofurans/pharmacology , Phosphodiesterase Inhibitors/chemical synthesis , Administration, Oral , Animals , Asthma/drug therapy , Benzamides/adverse effects , Benzamides/chemical synthesis , Benzamides/pharmacology , Benzofurans/adverse effects , Cyclic Nucleotide Phosphodiesterases, Type 4 , Eosinophilia/drug therapy , Guinea Pigs , Inhibitory Concentration 50 , Phosphodiesterase Inhibitors/adverse effects , Phosphodiesterase Inhibitors/pharmacology , Pyridines/adverse effects , Pyridines/chemical synthesis , Pyridines/pharmacology , Rolipram/adverse effects , Rolipram/analogs & derivatives , Rolipram/pharmacology , Structure-Activity Relationship , Vomiting/chemically inducedABSTRACT
Phosphodiesterase enzymes are responsible for the inactivation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterase 4 (PDE4) is a cAMP specific phosphodiesterase expressed in inflammatory cells such as eosinophils. Inhibition of PDE4 results in an elevation of cAMP in these cells, which in turn downregulates the inflammatory response. The anti-inflammatory effects of PDE4 inhibitors have been well documented both in vitro and in vivo in a variety of animal models. The potential use of PDE4 inhibitors as anti-inflammatory agents for the treatment of asthma and other inflammatory disorders has received considerable attention from the pharmaceutical industry, but to date, there are no selective PDE4 inhibitors on the market. Early PDE4 inhibitors, typified by rolipram, suffered from dose-limiting side effects, including nausea and emesis, which severely restricted their therapeutic utility. Second generation compounds, including CDP840 and SB207499 (Ariflo), have been identified with reduced side effect liability. Recent evidence suggests a correlation between side effects and the ability of compounds to bind at the so-called high affinity rolipram binding site (HPDE), whilst beneficial effects appear to correlate with binding at the catalytic site. A number of companies are actively pursuing compounds which exhibit improved affinity for the catalytic site and reduced affinity for the HPDE, in the expectation that this will provide compounds with an improved therapeutic index.
ABSTRACT
Novel xanthine analogues are described which are selective PDE4 inhibitors with improved therapeutic potential over theophylline.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Xanthines/chemical synthesis , Animals , Cyclic Nucleotide Phosphodiesterases, Type 4 , Eosinophilia/drug therapy , Ferrets , Guinea Pigs , Phosphodiesterase Inhibitors/adverse effects , Phosphodiesterase Inhibitors/pharmacology , Skin Diseases/drug therapy , Theophylline/pharmacology , Vomiting/chemically induced , Xanthines/pharmacologyABSTRACT
A series of novel selective phosphodiesterase 4 (PDE4) inhibitors has been developed which displays activity both in vitro and in vivo. These compounds possess good selectivity for the catalytic site of PDE4 over the high affinity Rolipram binding site. In vivo studies demonstrate a reduced propensity to display the emetic side effects which are commonly observed with PDE4 inhibitors.
