Pharmacological Characterization of a Novel Antiglaucoma Agent, Bimatoprost (AGN 192024)

Abstract

Replacement of the carboxylic acid group of prostaglandin (PG) F 2␣ with a nonacidic moiety, such as hydroxyl, methoxy, or amido, results in compounds with unique pharmacology. Bimatoprost (AGN 192024) is also a pharmacologically novel PGF 2␣ analog, where the carboxylic acid is replaced by a neutral ethylamide substituent. Bimatoprost potently contracted the feline lung parenchymal preparation (EC 50 value of 35-55 nM) but exhibited no meaningful activity in a variety of PG-sensitive tissue and cell preparations. Its activity seemed unrelated to FP receptor stimulation according to the following evidence. 1) Bimatoprost exhibited no meaningful activity in tissues and cells containing functional FP receptors. 2) Bimatoprost activity in the cat lung parenchyma is not species-specific because its potent activity in this preparation could not be reproduced in cells stably expressing the feline FP receptor. 3) Radioligand binding studies using feline and human recombinant FP receptors exhibited minimal competition versus [3 H]17-phenyl PGF 2a for Bimatoprost. 4) Bimatoprost pretreatment did not attenuate PGF 2␣ -induced Ca 2ϩ signals in Swiss 3T3 cells. 5) Regional differences were apparent for Bimatoprost but not FP agonist effects in the cat lung. Bimatoprost reduced intraocular pressure in ocular normotensive and hypertensive monkeys over a 0.001 to 0.1% dose range. A single-dose and multiple-dose ocular distribution/metabolism studies using [ 3 H]Bimatoprost (0.1%) were performed. Within the globe, bimatoprost concentrations were 10-to 100-fold higher in anterior segment tissues compared with the aqueous humor. Bimatoprost was overwhelmingly the predominant molecular species identified at all time points in ocular tissues, indicating that the intact molecule reduces intraocular pressure.Eicosanoids and related fatty acids have long been the subject of extensive investigation. More recently, it has become apparent that the corresponding neutral lipids exist for several fatty acids (Devane et al

Upregulation of orphan nuclear receptor Nur77 following PGF2α, Bimatoprost, and Butaprost treatments. Essential role of a protein kinase C pathway involved in EP2 receptor activated Nur77 gene transcription

“…Unlike PGF 2a and Butaprost, Bimatoprost did not upregulate Nur77 expression in human ciliary SM cells and TM cells and Nur77 would, therefore, be concluded to play no role in its ocular hypotensive effects. In our previous study, we found that Bimatoprost induced upregulation of Cyr61 gene expression in cat iris and human ciliary SM cells (Liang et al, 2003). In contrast to PGF 2a , Bimatoprost did not regulate either CTGF or Nur77 upregulation in human ciliary SM and TM cells.…”

Changes of orbital connective tissue after bimatoprost injection. Experimental study in rats

“…Therefore, if 1 ml of eyedrops (41 drops) contains 0.3 mg of bimatoprost, 1 droplet contains 0.007 mg, and 7 droplets contain 0.049 mg or 49 μg. Based on the study of Woodward et al (6) , this dose was safe for the animals. Woodward et al (6) used 2 droplets of bimatoprost 0.1% daily in monkeys weighting 2 kg, and this dose showed traces of metabolic substances in the blood of the animals, ensuring that this dose was not toxic.…”

“…PGF2 Ü is synthesized by a route involving COX-2 but not COX-1, suggesting a new route leading to the synthesis of endogenous lipid amides which reduce the intraocular pressure (IOP). Bimatoprost differs from prostaglandins as it does not stimulate the prostanoid receptors, is not mitogenic, does not contract the human uterus, and is electrochemically neutral (5,6) Clinical studies have reported ocular and periocular adverse events in 15 to 45% of patients receiving daily doses of eyedrops for three months. In decreasing order of incidence, the most adverse effects observed were: conjunctival hyperemia, growth of eyelashes and ocular pruritus 2 .…”

Interaction of Ocular Hypotensive Agents (PGF2α Analogs—Bimatoprost, Latanoprost, and Travoprost) With MDR Efflux Pumps on the Rabbit Cornea

“…[18][19][20][21] On the other hand, its metabolite, bimatoprost-free acid ) is also shown to lower the IOP by interacting with prostanoid FP receptors, thus being classifi ed as a potent FP receptor agonist. [22][23][24] On the contrary, both latanoprost and and MRP5 on the human as well as rabbit primary corneal epithelial cells. [6][7][8] In addition, mRNA expression levels of other isoforms of MRP, MRP1 and MRP3, have been reported in the human cornea, though functional activity and localization still remain to be assessed.…”