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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Biochemical and Pharmacological Characterization of 2-(9-(2-Piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071), a Novel, Orally Active Elastase Inhibitor

Zoltán Kapui, Márton Varga, Katalin Urban-Szabó, Endre Mikus, Tibor Szabó, Judit Szeredi, Sándor Bátori, Olivier Finance and Péter Arányi
Journal of Pharmacology and Experimental Therapeutics May 2003, 305 (2) 451-459; DOI: https://doi.org/10.1124/jpet.102.044263
Zoltán Kapui
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Márton Varga
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Katalin Urban-Szabó
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Endre Mikus
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Tibor Szabó
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Judit Szeredi
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Sándor Bátori
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Olivier Finance
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Péter Arányi
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Abstract

Human leukocyte elastase (HLE) is a proteinase capable of degrading a variety of proteins. Under normal circumstances, the proteolytic activity of HLE is effectively controlled by its natural inhibitors. However, an imbalance between elastase and its endogenous inhibitors may result in several pathophysiological states such as chronic obstructive pulmonary disease, asthma, emphysema, cystic fibrosis, and chronic inflammatory diseases. It is anticipated that an orally active HLE inhibitor could be useful for the treatment of these diseases. 2-(9-(2-Piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071) is a potent inhibitor of HLE, with the inhibition constant (Ki) and the constant for inactivation process (kon) being 0.0168 ± 0.0014 nM and 0.183 ± 0.013 106/mol sr, respectively. The dissociation rate constant, koff, was 3.11 + 0.37 10−6/s. SSR69071 displays a higher affinity for human elastase than for rat (Ki = 3 nM), mouse (Ki = 1.8 nM), and rabbit (Ki = 58 nM) elastases. Bronchoalveolar lavage fluid from mice orally treated with SSR69071 inhibits HLE (ex vivo), and in this model, SSR69071 has a dose-dependent efficacy with an ED50 = 10.5 mg/kg p.o. SSR69071 decreases significantly the acute lung hemorrhage induced by HLE (ED50 = 2.8 mg/kg p.o.) in mice. Furthermore, SSR69071 prevents carrageenan- (ED30 = 2.2 mg/kg) and HLE-induced (ED30 = 2.7 mg/kg) paw edema in rats after p.o. administration. In conclusion, SSR69071 is a selective, orally active, and potent inhibitor of HLE with good penetration in respiratory tissues.

Footnotes

  • DOI: 10.1124/jpet.102.044263

  • Abbreviations:
    HLE
    human neutrophil elastase
    PMNL
    polymorphonuclear leukocyte
    α1PI
    α1-protease inhibitor
    ARDS
    adult respiratory distress syndrome
    COPD
    chronic obstructive pulmonary disease
    BAL
    bronchoalveolar lavage
    MMP
    matrix metalloproteinase
    FK706
    sodium 2-[4-[[(S)-1-[[(S)-2-[[R,S)-3,3,3-trifluoro-1-isopropyl-2-oxopropyl]aminocarbonyl]pyrrolidin-1-yl]carbonyl]-2-methylpropyl]aminocarbonyl]benzoylamino]acetate
    ONO5046 (Sivelestat)
    sodiumN-[2-[4-(2,2-dimethylpropionyloxy)phenylsulfonylamino] benzoyl]aminoacetate tetrahydrate
    GW311616A
    (3S,3aS,6aR)-hexahydro-3-(1-methylethyl)-1-(methylsulfonyl)-4-[(2E)-1-oxo-4-(1-piperidinyl)-2-butenyl]-pyrrolo[3,2-b]pyrrol-2(1H)-one
    • Received September 30, 2002.
    • Accepted February 3, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 2
1 May 2003
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Biochemical and Pharmacological Characterization of 2-(9-(2-Piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071), a Novel, Orally Active Elastase Inhibitor
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Biochemical and Pharmacological Characterization of 2-(9-(2-Piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071), a Novel, Orally Active Elastase Inhibitor

Zoltán Kapui, Márton Varga, Katalin Urban-Szabó, Endre Mikus, Tibor Szabó, Judit Szeredi, Sándor Bátori, Olivier Finance and Péter Arányi
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 451-459; DOI: https://doi.org/10.1124/jpet.102.044263

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Biochemical and Pharmacological Characterization of 2-(9-(2-Piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071), a Novel, Orally Active Elastase Inhibitor

Zoltán Kapui, Márton Varga, Katalin Urban-Szabó, Endre Mikus, Tibor Szabó, Judit Szeredi, Sándor Bátori, Olivier Finance and Péter Arányi
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 451-459; DOI: https://doi.org/10.1124/jpet.102.044263
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