Thromboxane A2 Receptor Agonists

Short-Term Treatment of Ocular Hypertension A. Thromboxane A2 Receptor Agonists 

Title Thromboxane Ligands Without Blood Clotting Side Effects R.M. Burk et al, US Patent 7,019,149 (March 28, 2006) 

Utility Short-term Treatment of Intraocular Pressure 

Preparation of cyclopentane heptenoic acid, 5-cis-2-(3a-f-butyldimethyl-silyloxy-l-tra s-octenyl)-3,5-dihydroxy, [la, 2(1,3a, 5a]methyl ester 

A suspension of PGF2a (1.53 mmol) in 20 ml diethyl ether was cooled to 0°C, then treated dropwise with solution of diazomethane in diethyl ether until yellow color persisted. The solution was warmed to 25°C for 30 minutes, concentrated, and the ester used directly without any purification. 

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M. Takasuka, M. Kishi, M. Yamakawa, FTIR spectral study of intramolecular hydrogen bonding in thromboxane A2 receptor agonist (U-46619), prostaglandin (PG)E2, PGD2, PGF2.alpha., prostacyclin receptor agonist (carbacyclin) and their related compounds in dilute carbon tetrachloride solution Structure-activity relationships, J. Med. Chem. 37 (1994) 47. 

Fluoro prostaglandin, (IV), PGF2a analogs effective as thromboxane A2 receptor agonists were prepared by Klimko (3) and used in the treatment of glaucoma and ocular hypertension. 

Scheurlen M, Kirchner M, and Clemens MR., and Jasdionek K. (1993). Fish oil prq>arations ridi in docosahexaenoic acid modify platelet responsiveness to prostaglandin-endoperoxide/thromboxane A2 receptor agonists. Biochem. Pharmacol. 46,245-249. 

We observed recently that a relatively high concentration (300 pM) of phthalide 20 in rat PRP significantly inhibited platelet aggregation induced by collagen but not by ADP and U-46619 (a thromboxane A2 receptor agonist) [299]. The inconsistency between the previously reported data and our results may be due to the different species (rat versus rabbit) and preparations (platelet-rich plasma versus washed platelets) used. 

Defects in platelet-agonist interaction are exemplified by patients with impaired responses because of an abnormality at the level of platelet surface receptors for a specific agonist. Such receptor defects have been documented for epinephrine, collagert, ADP, and thromboxane A2. Hirata et al (21) have described an Arg 60 to Leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder. Evidence has been... 

In addition, since these compounds are competitive antagonists, the degree of antagonism of the thromboxane A2/prostaglandin endoperoxide receptor required to achieve a biological response will depend on the amount of agonist formed. Thus, a lack of a response to these compounds would not preclude a role for thromboxane A2 in a particular clinical setting. 

The binding of an agonist to a G-protein coupled receptor (GPCR), thromboxane A2, compared with thromboxane A2 reconstituted in PC/PS/... 

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