New Fluoroprostaglandin F2.ALPHA. Derivatives with Prostanoid FP-Receptor Agonistic Activity as Potent Ocular-Hypotensive Agents

Abstract

An elevated intraocular pressure (IOP) is one of the risk factors for the development of glaucoma. Recent prospective epidermal studies in the United States indicate that if IOP is lowered below 12 mmHg, 1) or by more than 30% from the baseline IOP in patients with normal-tension glaucoma, 2) the progress of the visual field defect can be delayed. Prostaglandin (PG) derivatives exert ocular-hypotensive effects through stimulation of prostanoid receptors (FP, DP, IP etc.) and possibly by activation of signal-transduction systems such as intracellular Ca 2ϩ and cyclic AMP. [3][4][5][6] One of the most potent PGF 2a derivatives at reducing IOP is latanoprost, a selective prostanoid FP-receptor agonist, and this drug has been successfully developed as an anti-glaucoma agent. 7) Recently, another selective prostanoid FP-receptor agonist, travoprost, was launched in the United States and other countries.8) Because of their potent, long-lasting ocular-hypotensive effects, prostanoid FP-receptor agonists are widely used for the treatment of glaucoma.However, clinical use over several years has revealed the existence of patients who do not respond well to PGF 2a derivatives. 9,10) In addition, long-term application of PGF 2a derivatives causes chronic adverse effects, such as iris/skin pigmentation, eyelash growth, and so on. [10][11][12][13][14][15][16][17][18][19] The PGF 2a -derivative-induced eye colour change is most likely due to an increased amount of melanin within iris stroma melanocytes. [20][21][22] These adverse effects may be related to the stimulation of prostanoid FP receptors in the eye. 3)To judge from the accumulating findings relating to latanoprost and other PGF 2a derivatives, prostanoid FP-receptor agonists are among the most promising ocular-hypotensive agents. To try to find prostanoid FP-receptor agonists that might be more potent at inducing an IOP reduction while causing fewer or weaker side effects than latanoprost, we synthesized new PGF 2a derivatives and evaluated their prostanoid FP-receptor-mediated activities both in vitro and in vivo. We report here some interesting new compounds with fluorine(s) in the 15-position of the PGF 2a -derivative structure. MATERIALS AND METHODS Materials Prostarumon® F injection 1000 (1 mg/ml PGF 2a ) was obtained from Ono Pharmaceutical Co., Ltd. (Osaka, Japan), while cloprostenol was from Cayman Chemical Co. (Ann Arbor, MI, U.S.A.). Latanoprost free acid, latanoprost, and free acid and ester forms of various PGF 2a derivatives (Table 1) Constriction of the Isolated Iris Sphincter in CatsA functional prostanoid FP-receptor-affinity assay was performed using iris sphincter muscles isolated from cat eyes. 23)This tissue expresses predominantly prostanoid FP receptors. 24,25) Male European cats (Charles River Japan, Kanagawa, Japan) weighing from 2.5 to 5.0 kg were sacrificed by injection of intravenous sodium pentobarbital (Dainippon Pharmaceutical Co., Ltd., Osaka, Japan). The eyes were immediately enucleated and placed into modified Krebs-Henseleit sol...

Disposition and Metabolism of a Novel Prostanoid Antiglaucoma Medication, Tafluprost, Following Ocular Administration to Rats

“…In the case of PGF 2␣ analogs, esterification of the prostaglandin ␣-chain carboxyl group sufficiently increases the lipophilicity of the molecule for it to traverse the cornea and/or sclera, where it is enzymatically hydrolyzed back to the active acid form for delivery to the ocular tissues and fluids (Madhu et al, 1998). In accord with such findings, the present studies have demonstrated that the novel 15,15-difluorinated PGF 2␣ ocular hypotensive agent tafluprost (Nakajima et al, 2003) acts as an efficient prodrug for tafluprost acid when applied topically to the eyes of albino rats, just as it does with related compounds such as latanoprost (Sjöquist et al, 1998). Hydrolysis of the ester to the pharmacologically active acid was both rapid and complete after ocular administration of tafluprost: the tritiated prodrug was not detected in eye tissues or plasma by radio-HPLC, whereas the acid form was effectively the only radioactive component in the cornea, aqueous humor, and iris/ciliary body for at least 8 h postdose.…”

“…Recent studies with 15-monofluorinated-and 15,15-difluorinated prostanoids showed that replacement of the hydroxyl group on that position with the halogen atom(s) can increase the desired FP-receptor-related activities while decreasing the side effects (Nakajima et al, 2003). Tafluprost [1-methylethyl (5Z)-7-{(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxy-1-butenyl]-3,5-dihydroxycyclopentyl}-5-heptenoate] (Fig.…”

“…Studies have shown that tafluprost is superior to latanoprost in several important pharmacological criteria (Nakajima et al, 2003;Takagi et al, 2004). Thus, in both ocular normotensive and laser-induced ocular hypertensive monkeys, a single instillation of 0.0025% tafluprost solution lowered IOP significantly more than 0.005% latanoprost.…”

Taflotan, the first preservative-free prostaglandin F2α analogue: treatment advantages in primary open-angle glaucoma patients

“…Он сочетает в себе максимальную эффективность (снижение внутриглазного дав-ления до 35 % при режиме дозирования один раз в сутки) с высоким профилем безопасности. Его молекула обладает бо льшим сродством к FP-рецепторам, что не только обес печивает более вы-раженный гипотензивный эффект, но и снижает выраженность местных побочных явлений, таких как гиперемия конъюнктивы и гиперпигмента-ция кожи век и радужной оболочки [22,28,33]. Есть данные о наличии у тафлупроста нейропро-текторного действия [34].…”

Prostanoids in the Therapy of Glaucoma

“…Consequently, these prostanoids are used in patients with glaucoma as the first-line of therapy. In addition to marketed prostanoids, another new prostanoid with FP-receptor agonist activity, tafluprost, will become available in the near future (33,34,37,56). A low incidence of systemic side effects is one of the reasons for the widespread use of prostanoids in the therapy of glaucoma.…”