1. 1,4-Cyclohexanecarboxylates: potent and selective inhibitors of phosophodiesterase 4 for the treatment of asthma.
- Author
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Christensen SB, Guider A, Forster CJ, Gleason JG, Bender PE, Karpinski JM, DeWolf WE Jr, Barnette MS, Underwood DC, Griswold DE, Cieslinski LB, Burman M, Bochnowicz S, Osborn RR, Manning CD, Grous M, Hillegas LM, Bartus JO, Ryan MD, Eggleston DS, Haltiwanger RC, and Torphy TJ
- Subjects
- Animals, Anti-Asthmatic Agents chemical synthesis, Anti-Asthmatic Agents metabolism, Anti-Asthmatic Agents toxicity, Anti-Inflammatory Agents, Non-Steroidal chemical synthesis, Anti-Inflammatory Agents, Non-Steroidal metabolism, Anti-Inflammatory Agents, Non-Steroidal toxicity, Binding, Competitive, Body Temperature drug effects, Brain metabolism, Bronchoconstriction drug effects, Cyclic Nucleotide Phosphodiesterases, Type 4, Cyclohexanecarboxylic Acids chemical synthesis, Cyclohexanecarboxylic Acids metabolism, Cyclohexanecarboxylic Acids toxicity, Dogs, Gastric Acid metabolism, Guinea Pigs, Humans, Mice, Monocytes drug effects, Monocytes metabolism, Nitriles, Phosphodiesterase Inhibitors chemical synthesis, Phosphodiesterase Inhibitors metabolism, Phosphodiesterase Inhibitors toxicity, Pyrrolidinones chemical synthesis, Pyrrolidinones metabolism, Pyrrolidinones pharmacology, Pyrrolidinones toxicity, Rabbits, Recombinant Proteins antagonists & inhibitors, Rolipram, Stereoisomerism, Structure-Activity Relationship, Tumor Necrosis Factor-alpha antagonists & inhibitors, Vomiting chemically induced, 3',5'-Cyclic-AMP Phosphodiesterases antagonists & inhibitors, Anti-Asthmatic Agents pharmacology, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Cyclohexanecarboxylic Acids pharmacology, Phosphodiesterase Inhibitors pharmacology
- Abstract
Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxyl ic acid (1, SB 207499, Ariflo), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.
- Published
- 1998
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