Tranilast

Description

Tranilast (53902-12-8) is an anti-allergy agent (inhibitor of mast cell degranulation) that has been shown to have potent immunomodulatory effects via inhibition of endotoxin induced: PGE2, IC50 = 1-20 μM; TXB2, IC50 = 10-50 μM; TGFβ1, IC50 = 100-200 μM; IL-8, IC50 = 100 μM .1-3 Tranilast also displays anti-angiogenic properties.4,5

Chemical Properties

Pale Green Solid

Originator

Rizaben,Kissei Pharmaceutical Co., Ltd.,Japan,1982

Uses

coronary vasodilator

Uses

Antiallergic drug, used to treat bronchial asthma, allergic rhinitis and atopic dermatitis.

Uses

Tranilast is a compound that exhibits anti-inflammatory and immunomodulatory effects by inhibiting lipid mediator and cytokine release from inflammatory cells and interfering with PDGF- and TGF-β1-induced proliferation and migration of vascular medial smooth muscle cells. Tranilast suppresses production of prostaglandin D2 (IC50 = 0.1 mM), prostaglandin E2 (IC50 = ~1-20 μM), thromboxane B2 (IC50 = ~10-50 μM), TGF-β1 (IC50 = ~100-200 μM), and interleukin-8 (IC50 = ~100 μM) in in vitro models as well as attenuates of the proinflammatory activity of human monocytes. While originally marketed as an antiallergenic drug, the efficacy of tranilast in preventing restenosis after percutaneous coronary intervention has been tested in a large-scale clinical trial. Additionally, tranilast inhibits VEGF-induced angiogenetic activities (i.e., proliferation, migration and tube formation of vascular endothelial cells) with IC50 values of 22, 18 and 193 μM, which may prove therapeutic for various retinal diseases.[Cayman Chemical]

Definition

ChEBI: An amidobenzoic acid that is anthranilic acid in which one of the anilino hydrogens is replaced by a 3,4-dimethoxycinnamoyl group.

Manufacturing Process

4 g of 3,4-dimethoxycinnamic acid was dissolved in 20 ml of dry pyridine. To this solution were added under cooling with ice and agitation 2 g of benzenesulfonyl chloride whereby a red orange precipitate was formed. The reaction mixture was stirred for about one hour and then 2 g of methyl anthranilate were added to the mixture under cooling with ice. The mixture was stirred for 2 hours at room temperature to complete the reaction. After completion of the reaction, the reaction mixture was concentrated and the residue was taken up in about 10 ml of chloroform. The solution was washed first with a 10% aqueous solution of caustic soda, then with a 10% aqueous solution of hydrochloric acid and finally with water and then distilled to remove chloroform whereby crystals of N-(3',4'-dimethoxycinnamoyl)- anthranilic acid methyl ester were obtained.
This product was dissolved in 10 ml of chloroform. To this solution were added 10 ml of a 10% aqueous solution of caustic soda and the mixture was warmed at 50°C to effect hydrolysis of the ester group. After completion of the reaction, the organic phase was separated, washed with water and distilled to remove the solvent whereby 2.1 g (yield: 48%) of the end product, i.e., N- (3',4'-dimethoxycinnamoyl)-anthranilic acid, were obtained. This product had a melting point of 211°C to 213°C

Therapeutic Function

Antiallergic

Biological Activity

Antiallergic via inhibition of chemical mediator release from mast cells. Most recently shown to be an effective inhibitor of angiogenesis. Demonstrated to antagonize the effects of angiotensin II on human arteries, possibly by an interaction at the level of the AT 1 receptor.

Biochem/physiol Actions

Tranilast also inhibits vascular smooth muscle cell proliferation by inhibiting the cyclin-dependent kinase inhibitor-1(p21Waf1/Cip1) and may be useful in treating cardiac allograft vasculopathy. It is used in treating hypertrophic scars and keloids. Tranilast inhibits tumor necrosis factor (TNF-α and TGF-β2), obstructing epithelial-mesenchymal transition in human retinal pigment epithelial cell line (ARPE).

storage

Room temperature

References

1) Capper et al. (2000) Modulation of human monocyte activities by tranilast, SB252218, a compound demonstrating efficacy in restenosis; J. Pharmacol. Exp. Ther., 38 2673 2) Ward et al., (2002) Tranilast prevents activation of transforming growth factor-b system, leukocyte accumulation and neointimal growth in porcine coronary arteries after stenting; Arterioscler. Thromb. Vasc. Biol., 22 940 3) Chikaraishi et al. (2001) Tranilast inhibits interleukin-1b-induced monocyte chemoattractant protein-1 expression in rat mesangial cells; Eur. J. Pharmacol., 427 151 4) Isaji et al. (1997) Tranilast inhibits the proliferation, chemotaxis and tube formation of human microvascular endothelial cells in vitro and angiogenesis in vivo; Br. J. Pharmacol., 122 1061 5) Koyama et al. (1999) Tranilast inhibits protein kinase C-dependent signaling pathway linked to angiogenic activities and gene expression of retinal microcapillary endothelial cells; Br. J. Pharmacol., 127 537