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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

BMS-229724 Is a Tight-Binding Inhibitor of Cytosolic Phospholipase A2 That Acts at the Lipid/Water Interface and Possesses Anti-Inflammatory Activity in Skin Inflammation Models

James R. Burke, Lynda B. Davern, Paul L. Stanley, Kurt R. Gregor, Jacques Banville, Roger Remillard, John W. Russell, Patrick J. Brassil, Mark R. Witmer, Graham Johnson, Jeffrey A. Tredup and Kenneth M. Tramposch
Journal of Pharmacology and Experimental Therapeutics July 2001, 298 (1) 376-385;
James R. Burke
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Lynda B. Davern
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Paul L. Stanley
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Kurt R. Gregor
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Jacques Banville
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Roger Remillard
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John W. Russell
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Patrick J. Brassil
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Mark R. Witmer
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Graham Johnson
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Jeffrey A. Tredup
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Kenneth M. Tramposch
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Abstract

Cytosolic phospholipase A2 (cPLA2) catalyzes the selective release of arachidonic acid from the sn-2 position of phospholipids and is believed to play a key cellular role in the generation of arachidonic acid. BMS-229724 (4-[4-[2-[2-[bis(4-chlorophenyl)methoxy]ethyl-sulfonyl]ethoxy]phenyl]-1,1,1-trifluoro-2-butanone) was found to be a selective inhibitor of cPLA2(IC50 = 2.8 μM) in that it did not inhibit secreted phospholipase A2 in vitro, nor phospholipase C and phospholipase D in cells. The compound was active in inhibiting arachidonate and eicosanoid production in U937 cells, neutrophils, platelets, monocytes, and mast cells. With a synthetic covesicle substrate system, the dose-dependent inhibition could be defined by kinetic equations describing competitive inhibition at the lipid/water interface. The apparent equilibrium dissociation constant for the inhibitor bound to the enzyme at the interface (KI*app) was determined to be 1 · 10−5 mol% versus an apparent dissociation constant for the arachidonate-containing phospholipid of 0.35 mol%. The unit of concentration in the interface is mole fraction (or mol%), which is related to the surface concentration of substrate, rather than bulk concentration that has units of molarity. Thus, BMS-229724 represents a novel inhibitor of cPLA2, which partitions into the phospholipid bilayer and competes with phospholipid substrate for the active site. This potent inhibition of the enzyme translated into anti-inflammatory activity when applied topically (5%, w/v) to a phorbol ester-induced chronic inflammation model in mouse ears, inhibiting edema and neutrophil infiltration, as well as prostaglandin and leukotriene levels in the skin. In hairless guinea pigs, BMS-229724 was active orally (10 mg/kg) in a UVB-induced skin erythema model in hairless guinea pigs.

Footnotes

  • 1 This equation is valid, since the active site dissociation constant for DMPM has been shown to be more than 330 times greater than the value for PAPC (Burke et al., 1997d).

  • 2 KM*appand KI*app are related to the intrinsic dissociation constants (KM* andKI*) by the equations:KM*app =KM* (1 + 1/KL*) and KI*app =KI* (1 + 1/KL*), where KL* is the active site dissociation constant for DMPM at the interface (Burke et al., 1997d).

  • 3 When determining the equilibrium dissociation constants from the active site, the mole amount of substrate ([14C]PAPC in this case) and the mole amount of DMPM were held constant, while varying the mole amount of inhibitor (Burke et al., 1995b, 1997d). This has the effect of actually decreasing the mole fraction of both substrate and DMPM as the inhibitor concentration is increased. Thus,XSO in eq. 1 equals the mole fraction of substrate phospholipid without inhibitor. The mole fraction of substrate in the presence of the inhibitor is correspondingly less.

  • 4 The partition coefficient,C, is defined as the concentration (molarity) of inhibitor in the phospholipid bilayer divided by the concentration in the aqueous phase.

  • ↵5 In eq. 2, M is defined as:M=IT1+1/KI*app1+XSo/KS*app where IT equals the total mole amount of inhibitor present. The definitions of all other variables are defined in the text.

  • Abbreviations:
    PLA2
    phospholipase A2
    cPLA2
    cytosolic PLA2
    sPLA2
    secreted PLA2
    LPS
    lipopolysaccharide
    DMPM
    1,2-dimyristoyl-sn-glycero-3-phosphomethanol
    PAPC
    1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine
    [14C]PAPC
    1-palmitoyl-2-arachidonoyl-[arachidonoyl-1-14C]-sn-glycero-3-phosphocholine
    fMLP
    N-formyl-methionyl-leucyl-phenylalanine
    PLC
    phospholipase C
    PLD
    phospholipase D
    IL
    interleukin
    TNFα
    tumor necrosis factor-α
    LTB4
    leukotriene B4
    PGE2
    prostaglandin E2
    PAF
    platelet-activating factor
    TPA
    12-O-tetradecanoylphorbol-13-acetate
    BisTris
    2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol
    AACOCF3
    arachidonyl trifluoromethyl ketone
    NF-κB
    nuclear factor-κB
    AP-1
    activating protein-1
    AUC
    area under the curve
    i.p.t.
    intraportal
    Vdss
    steady-state volume of distribution
    • Received February 2, 2001.
    • Accepted March 22, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 1
1 Jul 2001
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

BMS-229724 Is a Tight-Binding Inhibitor of Cytosolic Phospholipase A2 That Acts at the Lipid/Water Interface and Possesses Anti-Inflammatory Activity in Skin Inflammation Models

James R. Burke, Lynda B. Davern, Paul L. Stanley, Kurt R. Gregor, Jacques Banville, Roger Remillard, John W. Russell, Patrick J. Brassil, Mark R. Witmer, Graham Johnson, Jeffrey A. Tredup and Kenneth M. Tramposch
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 376-385;

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

BMS-229724 Is a Tight-Binding Inhibitor of Cytosolic Phospholipase A2 That Acts at the Lipid/Water Interface and Possesses Anti-Inflammatory Activity in Skin Inflammation Models

James R. Burke, Lynda B. Davern, Paul L. Stanley, Kurt R. Gregor, Jacques Banville, Roger Remillard, John W. Russell, Patrick J. Brassil, Mark R. Witmer, Graham Johnson, Jeffrey A. Tredup and Kenneth M. Tramposch
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 376-385;
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