Prostanoid Thromboxane

Bertolino F, Valentin J-P, Maffie M, Grelac F, Bessac A-M, Maclouf J, Delhon A, Levy-Toledano S, Patoiseau 7-F, Colpaert FC, John GW. Intrinsic activity of the non-prostanoid thromboxane Aj receptor antagonist, daltroban (BM 13,505), in human platelets in vitro and in ttie rat vasculature in vivo. Br J Pharmacol 1995 115 210-6... 

LEUKOTRIENE RECEPTOR AGONISTS act at receptors recognizing leukotrienes and analogues. The lipoxygenase system forms the leukotrienes, which are members of the eicosanoid family of phospholipid mediators. Their name derives from the fact that leukotrienes are found in leucocytes and contain a triene system of double bonds. The other members of the eicosanoid family are the prostanoids (thromboxanes and the prostaglandins), and these are formed by the cyclooxygenase system see cyclooxygenase INHIBITORS. All the eicosanoids are derived mainly from arachidonic acid. These mediators are synthesized on demand, and in some cases their half-lives are short. The... 

The prostanoid thromboxane (TP) receptor (TBXA2R) gene has been studied in asthma as a putative candidate gene due to its pharmacology. Thromboxane A2 (TXA2) binds to a specific receptor,... 

The ring expansion reaction has been used in multistep organic syntheses of natural products and analogs, most notably in the preparation of prostaglandins and prostanoids, thromboxane mimetics, and muscarine (Scheme 4). 

The enzyme system responsible for the biosynthesis of PGs is widely distributed in mammalian tissues and has been extensively studied (2). It is referred to as prostaglandin H synthase (PGHS) and exhibits both cyclooxygenase and peroxidase activity. In addition to the classical PGs two other prostanoid products, thromboxane [57576-52-0] (TxA ) (3) and prostacyclin [35121 -78-9] (PGI2) (4) are also derived from the action of the enzyme system on arachidonic acid (Fig. 1). 

Thromboxane A2 is a potent platelet aggregating agent and vasodilator which undergoes rapid hydrolysis under physiological conditions (ti/2 32 sec. at pH 7 and 37°C). The synthesis of stable analogs was of interest for biological studies of this potent but evanescent prostanoid. 

Cyclooxygenases. Figure 1 Pathways for the formation of prostanoids from arachidonic acid. Arachidonic acid is converted by cyclooxygenase to endoperoxides, which are acted upon by various synthesases to form the prostanoids. Prostacyclin and thromboxane are relatively unstable and break down rapidly to form the inactive metabolites 6-oxo-PGF1a and thromboxane B2, respectively. 

Eicosanoids These compounds, derived from eicosa- (20-carbon) polyenoic fatty acids, comprise the prostanoids, leukotrienes (LTs), and lipoxins (LXs). Prostanoids include prostaglandins (PGs), prostacyclins (PGIs), and thromboxanes (TXs). 

Capra, V., Habib, A., Accomazzo, M. R., et al. (2003) Thromboxane prostanoid receptor in human airway smooth muscle cells a relevant role in proliferation. Eur. J. Pharmacol. 474, 149-159. 

Citro, S., Ravasi, S., Rovati, G. E., and Capra, V. (2005) Thromboxane prostanoid receptor signals through G(i) protein to rapidly activate extracellular signal-regulated kinase in human airways. Am. J. Respir. Cell Mol. Biol. 32,326-333. 

The autacoids comprise histamine, serotonin, angiotensin, neurotensin, NO (nitric oxide), kinins, platelet-activating factor, endothelins and the four families of traditional eicosanoids - the leukotrienes and three types of prostanoids i.e. prostaglandins, prostacyclins, and thromboxanes. Several other natural occurring molecules are sometimes called eicos-anoid, including the hepoxilins, resolvins, isofurans, isoprostanes, lipoxins, epoxyeicosatrienoic acids (EETs) and some endocannabinoids. However, not... 

Prostanoids, which consist of prostaglandins (PCs) and thromboxanes (TXs), are biologically synthesized in the body from arachidonic acid by cyclooxygenase, PG hydroperoxydase, and a family of prostaglandin synthases (Fig. 1). They exert a variety of actions as hormones produced locally in various tissues and cells to maintain homeostasis. 

The prostaglandins, thromboxane, and prostacyclin, collectively termed the prostanoids, are generated from PGH2 through the... 

Certain structural indications of thromboxane A2 biosynthesis inhibition and hence potential therapeutic utility in arterial thrombosis prompted the synthesis of the pyridine prostanoid 544 (Scheme 165) (83TL3291). Brief metalation of 42 followed by DMF quench afforded aldehyde 541, which upon Homer-Emmons chain extension, reduction, and protection gave 542. Having served as a DMG, the bromo function was subjected to metal-halogen exchange, transmetalation (CuCN), and condensation with an iodo allene to furnish the 3,4-disubstituted pyridine 543. The latter was transformed into two derivatives 544 (with and without double bond), which were shown to be effective inhibitors of thromboxane A2. 

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