Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, V11294
| Autor: | Donald J. Kyle, Yakov Rotshteyn, E. A. M. Seeds, Clive P. Page, Gary Douglas, Perry V. Halushka, Mark Chasin, Donna Donigi Gale, Tatsui Matsumoto, David Cavalla, Ronald M. Burch, Katherine H Banner, Nandini Banik, Domenico Spina, Forrest L. Smith, Richard H. Wong, Selina Harrison, Peter Hofer, Stephan Jordan |
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| Rok vydání: | 2003 |
| Předmět: |
Pulmonary and Respiratory Medicine
Cyclic nucleotide phosphodiesterase Chemistry Phosphodiesterase Inhibitors Biochemistry (medical) Phosphodiesterase 3 Pharmacology In vitro Cyclic Nucleotide Phosphodiesterases Type 3 Cyclic Nucleotide Phosphodiesterases Type 4 Guinea pig In vivo 3' 5'-Cyclic-AMP Phosphodiesterases Purines medicine Animals Humans Pharmacology (medical) Bronchoconstriction medicine.symptom Rolipram medicine.drug Whole blood |
| Zdroj: | Pulmonary pharmacologytherapeutics. 16(2) |
| ISSN: | 1094-5539 |
| Popis: | V11294 is a new cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor of the rolipram class. In this report we present the pharmacological profile of V11294. V11294 inhibited PDE4 isolated from human lung with IC 50 405 nM, compared to 3700 nM for rolipram. In contrast, V11294 inhibition of human PDE3 and PDE5 occurred only at concentrations greater than 100,000 nM. Like rolipram, V11294 inhibited PDE4D more potently than other PDE4 subtypes. V11294, when incubated with human anticoagulated whole blood in vitro, or administered to mice, caused increased cAMP concentration, consistent with inhibition of PDE4. V11294 inhibited lectin-induced proliferation and lipopolysaccharide-induced TNFα synthesis by human adherent monocytes in vitro and inhibited lipopolysaccharide-induced TNFα synthesis in mice. V11294 caused relaxation of guinea pig isolated trachea and inhibited allergen-induced bronchoconstriction and eosinophilia in guinea pigs at doses of 1 and 3 mg/kg, p.o. In ferrets, V11294 was not emetogenic at doses up to 30 mg/kg, p.o., despite plasma concentration reaching 10-fold the IC 50 for PDE4. In contrast, rolipram induced severe retching and vomiting at 10 mg/kg, p.o. In conclusion, V11294 is an orally active PDE4 inhibitor that exhibits antiinflammatory activity in vitro, and in vivo at doses that are not emetogenic. |
| Databáze: | OpenAIRE |
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