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Pharmacology of a potent and selective inhibitor of PDE4 for inhaled administration.

Abstract
A strategy to overcome the side effect liabilities of oral PDE4 inhibitors has been to deliver the drugs by inhalation. In this report, we identify 1-[[5-(1(S)-aminoethly)-2-[8-methoxy-2-(triflurormethyl)-5-quinolinyl]-4-oxazolyl] carbonyl]-4(R)-[(cyclopropylcarbonyl)amino]-L-proline, ethyl ester xinafoate salt, (COMPOUND 1) as a potent and selective inhibitor of PDE4 with biological and pharmacokinetic properties suitable for delivery by the inhaled route. COMPOUND 1 potently inhibits human PDE4 (IC(50)=70pM) with little or no activity against other PDEs. It is highly potent against PDE4B and PDE4D which are important isoforms of PDE4 controlling inflammation and airway functions. In an allergen-challenged Brown Norway rat model of asthma, COMPOUND 1 inhibited the late phase influx of inflammatory cells and reductions in lung function following its administration by the intratracheal or nose-only routes of administration. Important differences were seen between intratracheal COMPOUND 1 and our previously published results with the oral PDE4 inhibitor roflumilast (Celly et al., 2005), as COMPOUND 1 rapidly (within 1h) reversed the decline in lung function when it was given therapeutically to rats already challenged with antigen. COMPOUND 1 was weakly active by the oral route which is a finding consistent with results showing this compound has poor oral bioavailability in animals. Positive interactions between COMPOUND 1 and albuterol, and COMPOUND 1 and mometasone furoate were seen on the improvement in lung functions in allergen-challenged rats. These results identify COMPOUND 1 as a potent and selective inhibitor of PDE4 with properties suitable for delivery by inhalation.
AuthorsRichard W Chapman, Aileen House, Jennifer Richard, Dan Prelusky, James Lamca, Peng Wang, Dan Lundell, Ping Wu, Pauline C Ting, Joe F Lee, Robert Aslanian, Jonathan E Phillips
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 643 Issue 2-3 Pg. 274-81 (Sep 25 2010) ISSN: 1879-0712 [Electronic] Netherlands
PMID20621091 (Publication Type: Journal Article)
Copyright2010 Elsevier B.V. All rights reserved.
Chemical References
  • 1-((5-(1-aminoethyl)-2-(8-methoxy-2-(triflurormethyl)-5-quinolinyl)-4-oxazolyl) carbonyl)-4-((cyclopropylcarbonyl)amino)proline ethyl ester
  • Aerosols
  • Anti-Allergic Agents
  • Anti-Inflammatory Agents
  • Bronchodilator Agents
  • Phosphodiesterase 4 Inhibitors
  • Powders
  • Quinolines
  • Tumor Necrosis Factor-alpha
  • Proline
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4B protein, human
  • PDE4D protein, human
Topics
  • Administration, Inhalation
  • Aerosols
  • Animals
  • Anti-Allergic Agents (administration & dosage, blood, pharmacokinetics, pharmacology)
  • Anti-Inflammatory Agents (therapeutic use)
  • Asthma (drug therapy, immunology, physiopathology)
  • Biological Availability
  • Bronchoalveolar Lavage Fluid (cytology)
  • Bronchodilator Agents (therapeutic use)
  • Cyclic Nucleotide Phosphodiesterases, Type 3 (metabolism)
  • Cyclic Nucleotide Phosphodiesterases, Type 4 (metabolism)
  • Drug Synergism
  • Half-Life
  • Humans
  • Leukocytes (drug effects, enzymology, metabolism)
  • Phosphodiesterase 4 Inhibitors (administration & dosage, blood, pharmacokinetics, pharmacology)
  • Powders
  • Proline (analogs & derivatives, pharmacology)
  • Quinolines (pharmacology)
  • Rats
  • Rats, Inbred BN
  • Tumor Necrosis Factor-alpha (metabolism)

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