Tafluprost

In the search for a new FP receptor agonist having more potent lOP-reducing activity and weaker side effects, our research group has recently discovered a 15-deoxy-15,15-difluoro-PGF2a derivative, tafluprost (AFP-168), which shows highly potent and selective affinity to the FP receptor [71],... 

In cultured melanoma cells, a carboxylic acid of latanoprost has been reported to increase melanogenesis [76], However, a carboxylic acid of tafluprost did not have the stimulatory effects on melanin content in cultured B16-F10 melanoma cells [72], It suggests the application of tafluprost may cause less pigmentation than do latanoprost. 

Fig. 7. Effects of tafluprost (AFP-168) and latanoprost on maximal reduction of intraocular pressure in conscious ocular normotensive monkeys. Reproduced with permission from Ref. [74]. Copyright 2004 Elsevier.

T. Ota, FI. Murata, E. Sugimoto, M. Aihara, M. Araie, Prostaglandin analogues and mouse intraocular pressure Effects of tafluprost, latanoprost, travoprost, and uno-prostone, considering 24-hour variation. Invest. Ophthalmol. Vis. Sci. 46 (2005) 2006. 

Fluorinated Prostanoids Development of Tafluprost, a New Anti-glaucoma Agent... 

Overall, AFP-172, the active carboxylic acid form of tafluprost, displayed the most potent activity. 

The affinity of the corresponding carboxylic acid of tafluprost for the recombinant human FP receptor expressed in clonal cells was 0.4 nM, which was 12 times and 1700 times... 

Since the acid form of tafluprost did not show significant affinities for other prostanoid receptors, the drug proved to be a highly selective compound [35]. Compared with the other prostanoids [26b, 36], tafluprost is regarded as one of the most selective prostanoid FP receptor agonists. 

Source Reprinted from Takagi, Y., Nakajima, /., Shimazaki, A., et al. Pharmacological characteristics of AFP-168 (tafluprost), a new prostanoid FP receptor agonist, as an ocular hypotensive drug. Exp. Eye Res., (2004) 78, 767-776, with permission from Elsevier)... 

Table 2.4 Effects of tafluprost on aqueous humor dynamics in anesthetized ocular normotensive monkeys...

Tafluprost significantly increases retinal blood flow and blood velocity in animal models. The improvement of ocular blood flow is thought to be relevant in glaucoma therapy, especially for normal-tension glaucoma patients since it is assumed that optic nerve damage is involved not only in mechanical compression caused by IOPbut also in impairment of ocular blood flow. 

The effects of tafluprost on IOP and retinal blood flow (RBF) were studied in adult cats [41]. A single drop of tafluprost was placed in one eye and IOP, vessel diameter, blood velocity, and RBF were measured simultaneously by laser Doppler velocimetry. Measurements carried out at 30 and 60min after dosing showed 16.1% and 21.0% IOP reduction, respectively, as well as 1% and 2.4% reduction in mean vessel diameter, respectively. The mean blood velocity increases were 17.4% and 13.7%, respectively, and the mean RBF increases were 20.7% and 18.8%, respectively, 30 and 60min after dosing. 

Another study aimed to evaluate and compare the effect of tafluprost, latanoprost, and travoprost on optic nerve head (ONH) blood flow in rabbits [42], A quantitative index of blood flow, squared blur rate (SBR), was determined with the laser speckle method, when 50pl of 0.0015% tafluprost, 0.005% latanoprost, or 0.004% travoprost were topically administrated once a daily for 28 days. After 28 days administration of tafluprost, latanoprost, and travoprost, the trough SBR values became 111.9 3.9%, 107.2 + 4.3% and 106.7 3.5%, respectively, compared with the value before administration. Sixty minutes after final administration on day 28, the SBR value with tafluprost, latanoprost, and travoprost become 116.1 + 3.5%, 106.1 3.0%, and 104.2 3.7%, respectively, compared with the value before administration. These results indicate that topical administrations of these compounds stably increase the ONH blood flow in rabbits. The magnitude of increase in ONH blood flow produced by tafluprost was greater than that of latanoprost or travoprost. 

Protective Effect of Tafluprost on Glutamate-Induced Cytotoxicity... 

The protective effect of tafluprost on the cytotoxicity and intracellular Ca2+ increase induced by 1-glutamate (Glu) using primary cultures obtained from the fetal rat retina has been reported [43], Tafluprost acid form significantly prevented Glu-induced cytotoxicity in a concentration-dependent manner of more than lOnM. However, latanoprost acid form did not show any effect on Glu-induced cytotoxicity. Tafluprost acid form showed the cell protective effect on Glu-induced cytotoxicity through the inhibition of intracellular Ca2+ increase in retinal cells. 

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