The next generation of PDE4 inhibitors.
A number of highly potent PDE4 inhibitors are being developed for the treatment of asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, multiple sclerosis and Crohn's disease. Cilomilast (Ariflo, SB 207499, SmithKline Beecham), the most advanced member of the class in Phase III clinical trials, was reported to have a limited therapeutic window. Other inhibitors with improved profiles in preclinical models are entering into (or are in) clinical trials. The recent developments in understanding PDE4 catalysis, inhibitor binding and their emetic response should facilitate the design of the next generation of PDE4 inhibitors.
Huang
Z
Z
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire, Dorval, Quebec, H9R 4P8, Canada. zheng_huang@merck.com
Ducharme
Y
Y
Macdonald
D
D
Robichaud
A
A
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000932:Antiemetics / Q000494:pharmacology; D002384:Catalysis; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
D000932:Antiemetics; D003509:Cyclohexanecarboxylic Acids; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; C433247:Cilomilast; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4