Inhibition of cellular action of thrombin by N3-cyclopropyl-7-{[4-(1-methylethyl)phenyl]methyl}-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (SCH 79797), a nonpeptide thrombin receptor antagonist

Ahn, Ho-Sam; Foster, Carolyn; Boykow, George; Stamford, Andrew W.; Manna, Mahua; Graziano, Michael P.

doi:10.1016/s0006-2952(00)00460-3

Cited by 136 publications

(74 citation statements)

References 48 publications

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“…SCH79797 and RWJ56110 have been described as pure PAR1 antagonists with the ability to inhibit both thrombin and PAR1 peptide agonists functional responses in different cells (Andrande-Gordon et al, 1999;Ahn et al, 2000), and their specificity has been confirmed in our hands. Of course, this does not exclude the possibility that, like any other, pharmacological agents have additional effects, which may limit their use as therapeutic agents.…”

supporting

confidence: 70%

Response to Comments on “Blockage of Angiogenesis by Small Molecule Antagonists to Protease-Activated Receptor-1: Association with Endothelial Cell Growth Suppression and Induction of Apoptosis”

Tsopanoglou¹,

Maragoudakis²

2007

J Pharmacol Exp Ther

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supporting

confidence: 70%

Response to Comments on “Blockage of Angiogenesis by Small Molecule Antagonists to Protease-Activated Receptor-1: Association with Endothelial Cell Growth Suppression and Induction of Apoptosis”

Tsopanoglou¹,

Maragoudakis²

2007

J Pharmacol Exp Ther

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“…The effect of PAR-1 antagonists on angiogenesis has not been reported. In the present study, we show that SCH79797 and RWJ56110, two well characterized specific and potent PAR-1 antagonists (Andrande-Gordon et al, 1999;Ahn et al, 2000), are capable of blocking angiogenesis in the chick embryo angiogenesis model in vivo and in the Matrigel in vitro system. We also show that these PAR-1 antagonists abrogate endothelial cell growth by induction of apoptosis.…”

mentioning

confidence: 50%

Blockade of Angiogenesis by Small Molecule Antagonists to Protease-Activated Receptor-1: Association with Endothelial Cell Growth Suppression and Induction of Apoptosis

Zania¹,

Kritikou²,

Flordellis³

et al. 2006

J Pharmacol Exp Ther

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Many studies support the notion that protease-activated receptor (PAR)-1 plays a pivotal role in angiogenesis. However, direct evidence and understanding the molecular mechanisms involved were limited because PAR-1-specific antagonists have been developed only recently. In the present study, we evaluated the effects of two well characterized PAR-1 antagonists,, in the angiogenic cascade. These antagonists suppressed both the basic angiogenesis and that stimulated by thrombin in the chick chorioallantoic membrane model in vivo. PAR-1 antagonists also abrogated tube formation in the in vitro Matrigel system. These inhibitory effects were dose-dependent and well correlated with the inhibitory effects of SCH79797 and RWJ56110 on primary endothelial cell proliferation and on the initiation of apoptosis. PAR-1 blockage resulted in inhibition of endothelial cell growth by increasing the sub-G 0 /G 1 fraction and reducing the percentage of cells in the S phase. Consistent with this, PAR-1 antagonists reduced incorporation of [ 3 H]thymidine in endothelial cells and blocked the phosphorylation of extracellular signal-regulated kinases in a fashion depending specifically on PAR-1 activation. Analysis by annexin V/propidium iodide staining and poly(ADP-ribose) polymerase cleavage revealed that PAR-1 blockage increased apoptotic cell death by a mechanism involving caspases. These results provide further evidence that PAR-1 is a key receptor that mediates angiogenesis and suggest PAR-1 as target for developing antiangiogenic agents with potential therapeutic application in cancer and other angiogenesis-related diseases.

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“…Although PAR1-mediated contractions occur in HCAs displaying signs of atheroma, 23 smooth muscle cell PARs may be involved in functions other than the regulation of vascular tone, such as smooth muscle growth and differentiation, 36 in the absence of atheroma.…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of Protease-Activated Receptor-2 (PAR2) and PAR4 in Human Coronary Artery by Inflammatory Stimuli Unveils Endothelium-Dependent Relaxations to PAR2 and PAR4 Agonists

Hamilton

Frauman

Cocks

2001

Circulation Research

135

112

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Abstract-Protease-activated receptor (PAR)1 and PAR2 are expressed on vascular endothelial cells and mediate endothelium-dependent relaxation in several species, and PAR4 agonists cause similar responses in rat aortas. To date, only PAR1 has been reported to mediate relaxation of human arteries despite endothelial cell expression of both PAR1 and PAR2 in these tissues. Because inflammatory stimuli increase PAR2 expression in human endothelial cells in culture, the present study investigated the effect of similar stimuli on PARs in human isolated coronary arteries (HCAs). In HCA ring segments suspended for isometric tension measurements, the selective PAR1-activating peptide, TFLLR (0.01 to 10 mol/L), caused endothelium-dependent relaxation of precontracted preparations. Little or no change in vascular tension was elicited by either the PAR2-or PAR4-activating peptides, SLIGKV and GYPGQV, respectively (up to 100 mol/L). Exposure of HCAs to interleukin (IL)-1␣ (1 ng/mL, 12 hours) or tumor necrosis factor-␣ (3 nmol/L, 12 hours) did not affect PAR1 expression but increased PAR2 and PAR4 mRNA levels by Ϸ5-and 4-fold, respectively, as determined by quantitative polymerase chain reaction. Similar IL-1␣ treatment did not affect TFLLR-induced relaxations but revealed significant endothelium-dependent relaxations to SLIGKV (100 mol/L, 61.4Ϯ6.7%) and GYPGQV (100 mol/L, 34.8Ϯ6.4%). These studies are the first to demonstrate functional PAR2 and PAR4 in human arteries in situ. The selective upregulation of PAR2 and PAR4 expression and the increased vascular response in HCAs after exposure to inflammatory stimuli suggest a role for these endothelial receptors during inflammation.

show abstract

Inhibition of cellular action of thrombin by N3-cyclopropyl-7-{[4-(1-methylethyl)phenyl]methyl}-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (SCH 79797), a nonpeptide thrombin receptor antagonist

Cited by 136 publications

References 48 publications

Response to Comments on “Blockage of Angiogenesis by Small Molecule Antagonists to Protease-Activated Receptor-1: Association with Endothelial Cell Growth Suppression and Induction of Apoptosis”

Response to Comments on “Blockage of Angiogenesis by Small Molecule Antagonists to Protease-Activated Receptor-1: Association with Endothelial Cell Growth Suppression and Induction of Apoptosis”

Blockade of Angiogenesis by Small Molecule Antagonists to Protease-Activated Receptor-1: Association with Endothelial Cell Growth Suppression and Induction of Apoptosis

Increased Expression of Protease-Activated Receptor-2 (PAR2) and PAR4 in Human Coronary Artery by Inflammatory Stimuli Unveils Endothelium-Dependent Relaxations to PAR2 and PAR4 Agonists

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