Bimatoprost (Lumigan), the ethyl amide derivative of the potent prostaglandin FP agonist 17-phenyl-trinor PGF(2alpha), has been reported to be a member of a pharmacologically unique class of ocular hypotensive agents. To confirm that bimatoprost, which is intrinsically active as an FP prostaglandin agonist, is also a prostaglandin analog prodrug, the hydrolysis of bimatoprost by ocular tissues was studied by incubating solutions containing bimatoprost with either human or rabbit ocular tissue. The ethyl amide group of bimatoprost was hydrolyzed by rabbit and human cornea, iris/ciliary body and Thasclera to produce the expected carboxylic acid product, 17-phenyl-trinor PGF(2alpha). The rate of hydrolysis by human and rabbit cornea and iris/ciliary body is similar, whereas the rate of hydrolysis by the sclera is slower in humans than in rabbits. These studies show that human and rabbit ocular tissue (cornea, iris/ciliary body and sclera) can convert bimatoprost to the potent prostaglandin FP agonist 17-phenyl-trinor PGF(2alpha). Separate in vitro studies clearly show that both bimatoprost and 17-phenyl-trinor PGF(2alpha) have affinity for and are agonists at the human FP receptor. Taken together, the data strongly suggests that the ocular hypotensive effect of bimatoprost can be attributed to its activity as a prostaglandin receptor agonist either directly or through its role as a prostaglandin agonist prodrug.

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A series of phenolic antioxidant ester and amide derivatives of the nonsteroidal antiinflammatory drug naproxen was designed to have both antiinflammatory and cytoprotective activity. Compounds were evaluated in vitro both for antioxidant activity, as assessed indirectly by thiobarbituric acid reactive substance (TBARS) formation in a membrane lipid peroxidation assay, and for antiproliferative activity, as indexed by the inhibition of DNA synthesis in cultured human vascular endothelial cells. Compounds of this series exhibited potent antioxidant activity, with IC50 values (1.6-11.63 microM) 2-6-fold lower than that of Trolox (6-hydroxy-2,5, 7,8-tetramethylchroman-2-carboxylic acid) and 400-1300-fold lower than that of vitamin E. Structural modifications of the ester or amide substructure (5a and 6a) did not affect antioxidant activity, but methylation of the 6-hydroxy substituent resulted in compound 6f which was devoid of antioxidant activity. Although indistinguishable in antioxidant activity, the amide derivatives tended to be more potent as antiproliferative agents than the corresponding esters. The IC50's for the amide derivatives (3, 5a-e, 8) ranged from 2 to 7 microM, while the IC50's for the structurally related esters (1, 2a-c, 6a-e) ranged from 9 to 22 microM. Moreover, studies with compound 6a indicate that the observed inhibition of DNA synthesis is reversible, suggesting that the antiproliferative activity is due to a cytostatic rather than cytotoxic activity of the compounds. Thus, the antioxidant-naproxen derivatives represent a novel series of agents that both protect against free-radical damage and possess cytostatic activity in vascular endothelial cells. Studies are in progress to assess the utility of these compounds as potential components of an ocular irrigating solution.

A method for the preparation of tritium labeled travoprost, a new ocular hypotensive prostaglandin, is described. A highly selective catalytic deiodination has been identified which provides [phenyl‐2‐3H]‐travoprost in a single synthetic step from 2′‐iodo‐travoprost. Copyright © 2001 John Wiley & Sons, Ltd.

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