title: 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.
authors.affiliation: Department of Bone, Respiratory, Immunology and Dermatology, Merck Research Laboratories, Kenilworth, New Jersey 07033, USA. richard.chapman@spcorp.com
authors.forename: Richard W
authors.initials: RW
authors.lastname: Chapman
authors.forename: Aileen
authors.initials: A
authors.lastname: House
authors.forename: Jennifer
authors.initials: J
authors.lastname: Richard
authors.forename: Dan
authors.initials: D
authors.lastname: Prelusky
authors.forename: James
authors.initials: J
authors.lastname: Lamca
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Dan
authors.initials: D
authors.lastname: Lundell
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Pauline C
authors.initials: PC
authors.lastname: Ting
authors.forename: Joe F
authors.initials: JF
authors.lastname: Lee
authors.forename: Robert
authors.initials: R
authors.lastname: Aslanian
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Phillips
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001682:Biological Availability; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D001993:Bronchodilator Agents / Q000627:therapeutic use; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D004357:Drug Synergism; D006207:Half-Life; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011208:Powders; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C554440:1-((5-(1-aminoethyl)-2-(8-methoxy-2-(triflurormethyl)-5-quinolinyl)-4-oxazolyl) carbonyl)-4-((cyclopropylcarbonyl)amino)proline ethyl ester; D000336:Aerosols; D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D058988:Phosphodiesterase 4 Inhibitors; D011208:Powders; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D011392:Proline; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; C517376:PDE4D protein, human