L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition

Z. Huang, R. Dias, T. Jones, S. Liu, A. Styhler, D. Claveau, F. Otu, K. Ng, F. Laliberte, L. Zhang, P. Goetghebeur, W. M. Abraham, D. Macdonald, D. Dubé, M. Gallant, P. Lacombe, Y. Girard, R. N. Young, M. J. Turner, D. W. NicholsonJ. A. Mancini

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 TNFα 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 IFNγ and no detectable inhibition of IL-13 formation up to 1 μM. 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.

Original languageEnglish
Pages (from-to)1971-1981
Number of pages11
JournalBiochemical Pharmacology
Volume73
Issue number12
DOIs
StatePublished - Jun 15 2007
Externally publishedYes

Fingerprint

Phosphodiesterase 4 Inhibitors
Cognition
Holoenzymes
Animals
Asthma
Animal Models
Blood
Type 4 Cyclic Nucleotide Phosphodiesterase
Pulmonary diseases
Interleukin-13
Ovalbumin
Inhibitory Concentration 50
Cytokines
Ascaris
Enzymes
Phosphodiesterase Inhibitors
Roflumilast
Chronic Obstructive Pulmonary Disease
Vomiting
Sheep

Keywords

  • Asthma
  • cAMP
  • Cognition
  • COPD
  • Inflammation
  • PDE4
  • Phosphodiesterase

ASJC Scopus subject areas

  • Pharmacology

Cite this

L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition. / Huang, Z.; Dias, R.; Jones, T.; Liu, S.; Styhler, A.; Claveau, D.; Otu, F.; Ng, K.; Laliberte, F.; Zhang, L.; Goetghebeur, P.; Abraham, W. M.; Macdonald, D.; Dubé, D.; Gallant, M.; Lacombe, P.; Girard, Y.; Young, R. N.; Turner, M. J.; Nicholson, D. W.; Mancini, J. A.

In: Biochemical Pharmacology, Vol. 73, No. 12, 15.06.2007, p. 1971-1981.

Research output: Contribution to journalArticle

Huang, Z, Dias, R, Jones, T, Liu, S, Styhler, A, Claveau, D, Otu, F, Ng, K, Laliberte, F, Zhang, L, Goetghebeur, P, Abraham, WM, Macdonald, D, Dubé, D, Gallant, M, Lacombe, P, Girard, Y, Young, RN, Turner, MJ, Nicholson, DW & Mancini, JA 2007, 'L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition', Biochemical Pharmacology, vol. 73, no. 12, pp. 1971-1981. https://doi.org/10.1016/j.bcp.2007.03.010
Huang, Z. ; Dias, R. ; Jones, T. ; Liu, S. ; Styhler, A. ; Claveau, D. ; Otu, F. ; Ng, K. ; Laliberte, F. ; Zhang, L. ; Goetghebeur, P. ; Abraham, W. M. ; Macdonald, D. ; Dubé, D. ; Gallant, M. ; Lacombe, P. ; Girard, Y. ; Young, R. N. ; Turner, M. J. ; Nicholson, D. W. ; Mancini, J. A. / L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition. In: Biochemical Pharmacology. 2007 ; Vol. 73, No. 12. pp. 1971-1981.
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AU - Otu, F.

AU - Ng, K.

AU - Laliberte, F.

AU - Zhang, L.

AU - Goetghebeur, P.

AU - Abraham, W. M.

AU - Macdonald, D.

AU - Dubé, D.

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