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.
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Authors | Richard 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 |
Journal | European journal of pharmacology
(Eur J Pharmacol)
Vol. 643
Issue 2-3
Pg. 274-81
(Sep 25 2010)
ISSN: 1879-0712 [Electronic] Netherlands |
PMID | 20621091
(Publication Type: Journal Article)
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Copyright | 2010 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
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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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