title: L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition.
abstract: Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a number of chronic disorders including asthma, chronic obstructive pulmonary disease (COPD) and cognitive disorders. This study delineates the preclinical profile of L-454,560, which is a potent, competitive and preferential inhibitor of PDE4A, 4B, and 4D with IC50 values of 1.6, 0.5 and 1.2 nM, respectively. In contrast to the exclusive binding of cilomilast and the preferential binding of roflumilast to the PDE4 holoenzyme state (Mg2+-bound form), L-454,560 binds to both the apo-(Mg2+-free) and holoenzyme states of PDE4. The intrinsic enzyme potency for PDE4 inhibition by L-454,560 also results in an effective blockade of LPS-induced TNFalpha formation in whole blood (IC50 = 161 nM) and is comparable to the human whole blood potency of roflumilast. The cytokine profile of inhibition of L-454,560 is mainly a Th1 profile with significant inhibition of IFNgamma and no detectable inhibition of IL-13 formation up to 1 microM. L-454,560 was also found to be efficacious in two models of airway hyper-reactivity, the ovalbumin (OVA) sensitized and challenged guinea pig and the ascaris sensitized sheep model. Furthermore, L-454560 was also effective in improving performance in the delayed matching to position (DMTP) version of the Morris watermaze, at a dose removed from that associated with potential emesis. Therefore, L-454,560 is a novel PDE4 inhibitor with an overall in vivo efficacy profile at least comparable to roflumilast and clearly superior to cilomilast.
authors.affiliation: Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
authors.forename: R
authors.initials: R
authors.lastname: Dias
authors.forename: T
authors.initials: T
authors.lastname: Jones
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: A
authors.initials: A
authors.lastname: Styhler
authors.forename: D
authors.initials: D
authors.lastname: Claveau
authors.forename: F
authors.initials: F
authors.lastname: Otu
authors.forename: K
authors.initials: K
authors.lastname: Ng
authors.forename: F
authors.initials: F
authors.lastname: Laliberte
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: P
authors.initials: P
authors.lastname: Goetghebeur
authors.forename: W M
authors.initials: WM
authors.lastname: Abraham
authors.forename: D
authors.initials: D
authors.lastname: Macdonald
authors.forename: D
authors.initials: D
authors.lastname: Dubé
authors.forename: M
authors.initials: M
authors.lastname: Gallant
authors.forename: P
authors.initials: P
authors.lastname: Lacombe
authors.forename: Y
authors.initials: Y
authors.lastname: Girard
authors.forename: R N
authors.initials: RN
authors.lastname: Young
authors.forename: M J
authors.initials: MJ
authors.lastname: Turner
authors.forename: D W
authors.initials: DW
authors.lastname: Nicholson
authors.forename: J A
authors.initials: JA
authors.lastname: Mancini
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000631:Aminopyridines / Q000097:blood / Q000494:pharmacology; D000818:Animals; D001051:Apoenzymes / Q000378:metabolism; D017165:Ascaris suum / Q000276:immunology; D001249:Asthma / Q000188:drug therapy*; D001549:Benzamides / Q000097:blood / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects; D002264:Carboxylic Acids / Q000494:pharmacology; D003072:Cognition Disorders / Q000188:drug therapy*; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids; D003521:Cyclopropanes / Q000097:blood / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D008297:Male; D015394:Molecular Structure; D009570:Nitriles / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012680:Sensitivity and Specificity; D012756:Sheep
chemical_list: D000631:Aminopyridines; D001051:Apoenzymes; D001549:Benzamides; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D003521:Cyclopropanes; C507187:L-454,560; D009570:Nitriles; D011804:Quinolines; C424423:Roflumilast; D007371:Interferon-gamma; C433247:Cilomilast; D010047:Ovalbumin; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517355:PDE4A protein, human