Identification and Characterization of the Ocular Hypotensive Efficacy of Travoprost, a Potent and Selective FP Prostaglandin Receptor Agonist, and AL-6598, a DP Prostaglandin Receptor Agonist

• Published in: Survey of Ophthalmology 2002-08, Vol.47, p.S13-S33
• Main Authors: Hellberg, Mark R., McLaughlin, Marsha A., Sharif, Naj A., DeSantis, Louis, Dean, Tom R., Kyba, Evan P., Bishop, John E., Klimko, Peter G., Zinke, Paul W., Selliah, Robert D., Barnes, George, DeFaller, Joseph, Kothe, Angela, Landry, Theresa, Sullivan, E.Kenneth, Andrew, Russell, Davis, Alberta A., Silver, Lewis, Bergamini, Michael V.W., Robertson, Stella, Weiner, Alan L., Sallee, Verney L.
• Format: Article
• Language: English
• Subjects: AL-6598; Animals; Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacology; Antihypertensive Agents - therapeutic use; Aqueous Humor - drug effects; Cats; Cloprostenol - analogs & derivatives; Cloprostenol - chemistry; Cloprostenol - pharmacology; Cloprostenol - therapeutic use; Dinoprost - analogs & derivatives; Dinoprost - chemistry; Dinoprost - pharmacology; Dinoprost - therapeutic use; Dose-Response Relationship, Drug; Female; glaucoma; Glaucoma, Open-Angle - drug therapy; Guinea Pigs; Humans; intraocular pressure; Intraocular Pressure - drug effects; Macaca fascicularis; Male; Ocular Hypertension - drug therapy; prostaglandin; prostaglandin analog; Rabbits; Randomized Controlled Trials as Topic; Receptors, Immunologic; Receptors, Prostaglandin - agonists; Safety; Structure-Activity Relationship; structure-activity relationships; Timolol - therapeutic use; Travoprost
• ISSN: 0039-6257; 1879-3304
• DOI: 10.1016/S0039-6257(02)00293-X

The structure-activity studies that led to the identification of travoprost, a highly selective and potent FP prostaglandin analog, and AL-6598, a DP prostaglandin analog, are detailed. In both series, the 1-alcohol analogs are very effective and are thought to be acting as prodrugs for the biologically active carboxylic acids. The efficacy of amide prodrugs depends on the degree of substitution and the size of the substituents. Selected compounds are profiled in vitro and in vivo preclinically. Clinical studies show that travoprost 0.004% (isopropyl ester) provided intraocular pressure control superior to timolol 0.5% when used as monotherapy in patients with open-angle glaucoma or ocular hypertension. In clinical studies, AL-6598 0.01% provided a sustained intraocular pressure reduction with q.d. application; b.i.d. provided greater intraocular pressure control. The acute and, apparently, conjunctival hyperemia associated with topical ocular AL-6598 can be attenuated while maintaining intraocular pressure-lowering efficacy by formulating with brimonidine.