Inhibition of allergen-induced pulmonary responses by the selective tryptase inhibitor 1,5-bis-{4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-phenoxy}-pentane (AMG-126737)

Wright, Clifford D.; Havill, Andrew M.; Middleton, Scot; Kashem, Mohammed A.; Dripps, David J.; Abraham, William M.; Thomson, D. S.; Burgess, Laurence E.

doi:10.1016/s0006-2952(99)00304-4

Cited by 65 publications

(22 citation statements)

References 36 publications

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“…Based on these findings, APC-366 underwent a clinical trial for the indication of asthma but the outcome of this trial was relatively disappointing (Krishna et al, 2001). Since then, several tryptase inhibitors of higher efficacy and with higher selectivity for tryptase have been developed and have been shown to have efficacy in models of airway inflammation (Costanzo et al, 2008; Oh et al, 2002; Wright et al, 1999). Moreover, studies in humans have shown that a highly selective tryptase inhibitor (APC-2059) can ameliorate ulcerative colitis to some extent (Tremaine et al, 2002) and that a dual inhibitor of tryptase and pancreatic trypsin (RWJ-58643) can diminish nasal allergic responses (Erin et al, 2006).…”

Section: Nongenetic Approaches For Analyzing the Functions Of Mastmentioning

confidence: 99%

Approaches for Analyzing the Roles of Mast Cells and Their Proteases In Vivo

Galli

Tsai

Marichal

et al. 2015

Advances in Immunology

101

110

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The roles of mast cells in health and disease remain incompletely understood. While the evidence that mast cells are critical effector cells in IgE-dependent anaphylaxis and other acute IgE-mediated allergic reactions seems unassailable, studies employing various mice deficient in mast cells or mast cell-associated proteases have yielded divergent conclusions about the roles of mast cells or their proteases in certain other immunological responses. Such “controversial” results call into question the relative utility of various older versus newer approaches to ascertain the roles of mast cells and mast cell proteases in vivo. This review discusses how both older and more recent mouse models have been used to investigate the functions of mast cells and their proteases in health and disease. We particularly focus on settings in which divergent conclusions about the importance of mast cells and their proteases have been supported by studies that employed different models of mast cell or mast cell protease deficiency. We think that two major conclusions can be drawn from such findings: (1) no matter which models of mast cell or mast cell protease deficiency one employs, the conclusions drawn from the experiments always should take into account the potential limitations of the models (particularly abnormalities affecting cell types other than mast cells) and (2) even when analyzing a biological response using a single model of mast cell or mast cell protease deficiency, details of experimental design are critical in efforts to define those conditions under which important contributions of mast cells or their proteases can be identified.

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Section: Nongenetic Approaches For Analyzing the Functions Of Mastmentioning

confidence: 99%

Approaches for Analyzing the Roles of Mast Cells and Their Proteases In Vivo

Galli

Tsai

Marichal

et al. 2015

Advances in Immunology

101

110

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“…β-Tryptase activity is inhibited by small synthetic inhibitors such as diisopropylfluorophosphate, phenylmethylsulfonyl fluoride, tosyl-L-lysine chloromethyl ketone and leupeptin [1]. Several synthetic β-tryptase inhibitors were shown in vivo to reduce Ag-induced airway hypersensitivity in sheep [35,36], pig [37] and mouse [38], which indicates tryptase may be involved in the pathogenesis of airway inflammation.…”

Section: Inhibitors and Target Proteinsmentioning

confidence: 99%

Active monomers of human β-tryptase have expanded substrate specificities

Fukuoka

Schwartz

2007

International Immunopharmacology

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Abstractβ-Tryptase, a product of the TPSAB1 and TPSB2 genes, is a trypsin-like serine protease that is a major and selective component of the secretory granules of all human mast cells, accounting for as much as 25% of cell protein. Once mast cells are activated, β-tryptase is released along with histamine and heparin proteoglycan. β-Tryptase is a unique enzyme with a homotetrameric structure in which active sites face into the central cavity of the four monomers, stabilized by heparin-proteoglycan. This structure makes β-tryptase resistant to most biological inhibitors of serine proteases. Without stabilization, at neutral pH β-tryptase converts to inactive monomers. Tryptase levels are elevated in bronchoalveolar lavage (BAL) fluid obtained from atopic asthmatics and in serum during systemic anaphylactic shock. Several synthetic small molecular weight β-tryptase inhibitors reduced Aginduced airway hypersensitivity in animals, suggesting β-tryptase is involved in the pathogenesis of airway inflammation. Although the major biologic substrate(s) of β-tryptase remain ambiguous, the protease can digest several proteins of potential biologic importance, including fibrinogen, fibronectin, pro-urokinase, pro-matrix metalloprotease-3 (proMMP-3), protease activated receptor-2 (PAR2) and complement component C3. Recently, monomers of β-tryptase with enzymatic activity have been detected in vitro. Here we discuss how β-tryptase monomers with enzymatic activity were identified as well as their potential role in vivo.

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“…Administration of inhibitors of tryptase to sheep and guinea pig models of allergic airways disease has been reported to reduce allergen-induced early increases in specific lung resistance (Clark et al, 1995;Wright et al, 1999) consistent with inhibition of mast cell activation. Also reduced in these animal models were the late phase increases in lung resistance and airways hyper-responsiveness.…”

mentioning

confidence: 98%

Inhibitors of Tryptase as Mast Cell-Stabilizing Agents in the Human Airways: Effects of Tryptase and Other Agonists of Proteinase-Activated Receptor 2 on Histamine Release

He¹,

Aslam²,

Gaça³

et al. 2004

J Pharmacol Exp Ther

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Tryptase, the major secretory product of human mast cells, is emerging as a new target for therapeutic intervention in allergic airways disease. We have investigated the ability of tryptase and inhibitors of tryptase to modulate histamine release from human lung mast cells and have examined the potential contribution of proteinase-activated receptor 2 (PAR2). The tryptase inhibitor APC366 [N-(1-hydroxy-2-naphthoyl)-L-arginyl-L-prolinamide hydrochloride] was highly effective at inhibiting histamine release stimulated by antiIgE antibody or calcium ionophore from enzymatically dispersed human lung cells. A concentration of APC366 as low as 10 M was able to inhibit anti-IgE-dependent histamine release by some 50%. Addition of leupeptin or the tryptic substrate N-benzoyl-D,L-arginine-p-nitroanilide also inhibited IgE-dependent histamine release. Purified tryptase in the presence of heparin stimulated a small but significant release of histamine from lung cells, suggesting that tryptase may provide an amplification signal from activated cells that may be susceptible to proteinase inhibitors. Trypsin was also able to induce histamine release apparently by a catalytic mechanism. Moreover, pretreatment of cells with metabolic inhibitors or with pertussis toxin reduced responses, indicating a noncytoxic pertussis toxin-sensitive G proteinmediated signaling process. Addition to cells of the PAR2 agonists SLIGKV-NH 2 or tc-LIGRLO-NH 2 or appropriate control peptides were without effect on histamine release, and PAR2 was not detected by immunohistochemistry in tissue mast cells. The potent actions of tryptase inhibitors as mast cell-stabilizing agents could be of value in the treatment of allergic inflammation of the respiratory tract, possibly by targeting the non-PAR2-mediated actions of tryptase.

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Inhibition of allergen-induced pulmonary responses by the selective tryptase inhibitor 1,5-bis-{4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-phenoxy}-pentane (AMG-126737)

Cited by 65 publications

References 36 publications

Approaches for Analyzing the Roles of Mast Cells and Their Proteases In Vivo

Approaches for Analyzing the Roles of Mast Cells and Their Proteases In Vivo

Active monomers of human β-tryptase have expanded substrate specificities

Inhibitors of Tryptase as Mast Cell-Stabilizing Agents in the Human Airways: Effects of Tryptase and Other Agonists of Proteinase-Activated Receptor 2 on Histamine Release

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