دورية أكاديمية
In vivo characterization of GSK256066, a high-affinity inhaled phosphodiesterase 4 inhibitor.
| العنوان: | In vivo characterization of GSK256066, a high-affinity inhaled phosphodiesterase 4 inhibitor. |
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| المؤلفون: | Nials AT; UK Discovery Biology, Respiratory Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Ltd, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, United Kingdom SG1 2NY. tony.t.nials@gsk.com, Tralau-Stewart CJ, Gascoigne MH, Ball DI, Ranshaw LE, Knowles RG |
| المصدر: | The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2011 Apr; Vol. 337 (1), pp. 137-44. Date of Electronic Publication: 2011 Jan 04. |
| نوع المنشور: | Comparative Study; Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0376362 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0103 (Electronic) Linking ISSN: 00223565 NLM ISO Abbreviation: J Pharmacol Exp Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1999- : Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics Original Publication: Baltimore : Williams & Wilkins |
| مواضيع طبية MeSH: | Aminoquinolines/*administration & dosage , Cyclic Nucleotide Phosphodiesterases, Type 4/*metabolism , Phosphodiesterase 4 Inhibitors/*administration & dosage , Sulfones/*administration & dosage, Administration, Inhalation ; Aminoquinolines/metabolism ; Animals ; Eosinophilia/drug therapy ; Eosinophilia/enzymology ; Ferrets ; Male ; Phosphodiesterase 4 Inhibitors/metabolism ; Rats ; Rats, Inbred BN ; Rats, Sprague-Dawley ; Sulfones/metabolism |
| مستخلص: | Oral phosphodiesterase (PDE) 4 inhibitors have demonstrated clinical efficacy in chronic obstructive pulmonary disease and asthma. Preclinical and clinical investigation of inhaled PDE4 inhibitors is ongoing. 6-({3-[(Dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-methyloxy)phenyl]amino}-3-quinolinecarboxamide (GSK256066) is an exceptionally high-affinity and selective inhibitor of PDE4 designed for inhaled delivery. The aim of these studies was to investigate the potency, duration of action, and therapeutic index of GSK256066 in animal models of pulmonary inflammation. The effects of intratracheally administered GSK256066 were investigated in rat lipopolysaccharide (LPS)- and ovalbumin (OVA)-induced models of acute pulmonary inflammation. In some studies, fluticasone propionate (FP) was included as a comparator. The therapeutic index (anti-inflammatory effect versus emesis) of GSK256066 was studied in ferrets where acute pulmonary inflammation was induced with inhaled LPS. In rats, GSK256066 and FP caused significant (p < 0.05) inhibition of LPS-induced pulmonary neutrophilia. The duration of action of GSK256066 at 10 × ED(50) dose (10 μg/kg) was 12 h. GSK256066 and FP also inhibited LPS-induced increases in exhaled nitric oxide (ED(50) 35 and 92 μg/kg, respectively). In addition, GSK256066 inhibited pulmonary eosinophilia in rats exposed to OVA (ED(50) 0.4 μg/kg). In ferrets, inhaled GSK256066 inhibited LPS-induced pulmonary neutrophilia (ED(50) 18 μg/kg), and no emetic episodes were observed. Thus, GSK256066 may have an improved therapeutic index compared with oral PDE4 inhibitors, e.g., cilomilast and roflumilast. In summary, GSK256066 demonstrates potent and long-lasting anti-inflammatory effects in animal models of pulmonary inflammation and does not induce emetic episodes in ferrets. GSK256066 has potential as an inhaled therapeutic for the treatment of asthma and chronic obstructive pulmonary disease. |
| المشرفين على المادة: | 0 (6-((3-((dimethylamino)carbonyl)phenyl)sulfonyl)-8-methyl-4-((3-methyloxyphenyl)amino)-3-quinolinecarboxamide) 0 (Aminoquinolines) 0 (Phosphodiesterase 4 Inhibitors) 0 (Sulfones) EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4) |
| تواريخ الأحداث: | Date Created: 20110106 Date Completed: 20110519 Latest Revision: 20110323 |
| رمز التحديث: | 20240829 |
| DOI: | 10.1124/jpet.110.173641 |
| PMID: | 21205924 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-0103 |
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| DOI: | 10.1124/jpet.110.173641 |