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

European Journal of Pharmacology
Richard W ChapmanJonathan E Phillips

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...Continue Reading

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Citations

Sep 8, 2011·BMC Medicine·Neil C ThomsonMark Spears
Apr 7, 2011·International Journal of Chronic Obstructive Pulmonary Disease·Sabina Antonela Antoniu
Sep 29, 2011·Future Medicinal Chemistry·Matthew D SelbyDannielle F Roberts
May 10, 2013·American Journal of Respiratory and Critical Care Medicine·Bianca BeghèLeonardo M Fabbri
Dec 19, 2015·Expert Review of Respiratory Medicine·Neil C Thomson
Feb 14, 2012·International Immunopharmacology·Lan XuQiang-min Xie
Jan 19, 2017·Expert Opinion on Pharmacotherapy·Neil C Thomson
Mar 2, 2016·Therapeutic Advances in Respiratory Disease·Neil C Thomson
May 23, 2012·Pharmacological Reviews·Mario CazzolaM Gabriella Matera
Jan 6, 2011·The Journal of Pharmacology and Experimental Therapeutics·Anthony T NialsRichard G Knowles
Feb 12, 2014·The Journal of Pharmacology and Experimental Therapeutics·Stacey L TannheimerMichael Salmon
Apr 1, 2020·Frontiers in Pharmacology·Jonathan E Phillips
Aug 15, 2012·Journal of Medicinal Chemistry·Neil J PressAlexandre Trifilieff

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