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Research ArticleDrug Discovery and Translational Medicine

AZD9668: Pharmacological Characterization of a Novel Oral Inhibitor of Neutrophil Elastase

T. Stevens, K. Ekholm, M. Gränse, M. Lindahl, V. Kozma, C. Jungar, T. Ottosson, H. Falk-Håkansson, A. Churg, J. L. Wright, H. Lal and A. Sanfridson
Journal of Pharmacology and Experimental Therapeutics October 2011, 339 (1) 313-320; DOI: https://doi.org/10.1124/jpet.111.182139
T. Stevens
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K. Ekholm
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M. Gränse
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M. Lindahl
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V. Kozma
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C. Jungar
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T. Ottosson
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H. Falk-Håkansson
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A. Churg
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J. L. Wright
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H. Lal
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A. Sanfridson
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Abstract

N-{[5-(methanesulfonyl)pyridin-2-yl]methyl}-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (AZD9668) is a novel, oral inhibitor of neutrophil elastase (NE), an enzyme implicated in the signs, symptoms, and disease progression in NE-driven respiratory diseases such as bronchiectasis and chronic obstructive pulmonary disease via its role in the inflammatory process, mucus overproduction, and lung tissue damage. In vitro and in vivo experiments were done to evaluate the binding kinetics, potency, and selectivity of AZD9668, its effects in whole-blood and cell-based assays, and its efficacy in models of lung inflammation and damage. In contrast to earlier NE inhibitors, the interaction between AZD9668 and NE was rapidly reversible. AZD9668 was also highly selective for NE over other neutrophil-derived serine proteases. In cell-based assays, AZD9668 inhibited plasma NE activity in zymosan-stimulated whole blood. In isolated human polymorphonuclear cells, AZD9668 inhibited NE activity on the surface of stimulated cells and in the supernatant of primed, stimulated cells. AZD9668 showed good crossover potency to NE from other species. Oral administration of AZD9668 to mice or rats prevented human NE-induced lung injury, measured by lung hemorrhage, and an increase in matrix protein degradation products in bronchoalveolar lavage (BAL) fluid. In an acute smoke model, AZD9668 reduced the inflammatory response to cigarette smoke as indicated by a reduction in BAL neutrophils and interleukin-1β. Finally, AZD9668 prevented airspace enlargement and small airway wall remodeling in guinea pigs in response to chronic tobacco smoke exposure whether dosed therapeutically or prophylactically. In summary, AZD9668 has the potential to reduce lung inflammation and the associated structural and functional changes in human diseases.

Footnotes

  • This study was funded by AstraZeneca.

  • Portions of this work appeared previously as a meeting abstract: Sanfridson A, Ottosson T, Ekholm K, Jungar C, Granse M, Kozma V, Falk Hakansson H, Lal H, and Stevens T (2010) AZD9668: pharmacological characterization of a novel oral inhibitor of neutrophil elastase (NE), at the European Respiratory Society Annual Congress; 2010 Sept 18–22; Barcelona, Spain. Abstract 5150, 942s. European Respiratory Society, Lausanne, Switzerland.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.182139.

  • ABBREVIATIONS:

    COPD
    chronic obstructive pulmonary disease
    α1-AT
    α1-antitrypsin
    BAL
    bronchoalveolar lavage
    catG
    cathepsin G
    fMLP
    fMet-Leu-Phe
    IL
    interleukin
    LPS
    lipopolysaccharide
    NE
    neutrophil elastase
    Pr-3
    proteinase-3
    CF
    cystic fibrosis
    ANOVA
    analysis of variance
    AZD9668
    N-{[5-(methanesulfonyl)pyridin-2-yl]methyl}-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide
    ONO6818
    N-[2-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-(1RS)-1-(methylethyl)-2-oxoethyl]-2-(5-amino-6-oxo-2-phenyl-6H-pyrimidin-1-yl) acetamide
    ONO5046
    N-{2-[({4-[(2,2-dimethylpropanoyl)oxy]phenyl}sulfonyl)amino]benzoyl}glycine
    MR889
    2-(2-thiophencarboxythio)-N-[dihydro-2(3H)-thiophenone-3-yl]-propionamide
    ZD0892
    N-(4-methoxybenzoyl)-l-valyl-N-[3,3,3-trifluoro-(1S)-(1-methylethyl)-2-oxopropyl]-l-prolinamide.

  • Received March 31, 2011.
  • Accepted July 25, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 1
1 Oct 2011
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Research ArticleDrug Discovery and Translational Medicine

Preclinical Pharmacology of AZD9668, a Novel NE Inhibitor

T. Stevens, K. Ekholm, M. Gränse, M. Lindahl, V. Kozma, C. Jungar, T. Ottosson, H. Falk-Håkansson, A. Churg, J. L. Wright, H. Lal and A. Sanfridson
Journal of Pharmacology and Experimental Therapeutics October 1, 2011, 339 (1) 313-320; DOI: https://doi.org/10.1124/jpet.111.182139

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Research ArticleDrug Discovery and Translational Medicine

Preclinical Pharmacology of AZD9668, a Novel NE Inhibitor

T. Stevens, K. Ekholm, M. Gränse, M. Lindahl, V. Kozma, C. Jungar, T. Ottosson, H. Falk-Håkansson, A. Churg, J. L. Wright, H. Lal and A. Sanfridson
Journal of Pharmacology and Experimental Therapeutics October 1, 2011, 339 (1) 313-320; DOI: https://doi.org/10.1124/jpet.111.182139
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