R-flurbiprofen

The syndecan family of heparin sulfate proteoglycans (HSPGs) plays critical roles in several signal transduction pathways, and syndecan 3 intramembrane proteolysis is presenilin/y-secretase dependent (357). COX2 and COXl potentiate ABP formation through mechanisms that involve y-secretase activity. Sulindac sulfide and other NSAIDs (ibuprofen, indomethacin, R-flurbiprofen) selectively decrease the secretion of ABP independently of COX activity, probably via y-secretase inhibition (358-360). Pepstatin A methylester, sulfonamides, and benzodiazepines can also act as potent, noncompetitive, y-secretase inhibitors (335). These are but a few examples of the potential repercussions and biochemical consequences that the pharmacological manipulation of secretases in AD may bring about. 

These NSAID MPC-7869 (R)-flurbiprofen) is a drug candidate (Phase III) for Alzheimer disease. It affects jS-amyloid deposition and metabolism and prevents cognitive deficits in transgenic animals. It is also being evaluated in hormone-naive prostate cancer (cf. infra). ... 

In addition to COX inhibition, flurbiprofen shows weak inhibition of the transcription factors NF-kB and AP-1. This activity resides in the R-enantiomer which has no COX-inhibiting properties (Tegeder et al., 2001). The clinical relevance of this activity is unknown. Furthermore, the anti-proliferative potential of R-flurbiprofen has been investigated in the treatment of cancer (Wechter et al., 2000). 

Greenberg, N. M. E-7869 (R-flurbiprofen) inhibits progression of prostate cancer in the TRAMP mouse, Cancer Res. 2000, 60, 2203-2208. 

Flurbiprofen is a cyclooxygenase (COX)-inhibiting non-steroidal anti-inflammatory drug (NSAID). The COX-inhibiting activity resides primarily in the (S)-enantiomer whereas the (R)-enantiomer has scarce COX activity. (R)-Flurbiprofen has been found to inhibit tumor growth in various animal models. In vitro experiments have shown that this effect is based on the induction of a cell cycle block and apoptosis [21]. 

Because chronic inflammation is associated with AD, several anti-inflamatory drugs have been tested including celecoxib (sc-125 sc-560), r-flurbiprofen, naproxen, and rocoxib (Szekely et al., 2004). Unfortunately, no consistent improvement in AD symptoms after treatment has been reported. 

Kukar, T., Prescott, S., Eriksen, J. L., Holloway, V., Murphy, M. R, Koo, E. H., Golde, T. E., Nicolle, M. M. Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci. 2007, 8, 54. 

Enantiomeric competition for protein binding has also been reported for flurbiprofen enantiomers in rats, with displacement of R-flurbiprofen by its antipode from plasma proteins [268]. Jamali et al. [246] postulated that the interaction between enantiomers of flurbiprofen at protein binding level may explain the increase in the clearance of R-flurbiprofen. However, a more recently published study indicates that the extent of pharmacokinetic interaction between flurbiprofen enantiomers is not significant in humans [269]. 

Geisslinger, G. Ferreira, S.H. Menzel, S. Schlott, D. Brune, K. Antinociceptive actions of R(—)-flurbiprofen—a non-cyclooxygenase inhibiting 2-arylpropionic acid—in rats. Life Sci. 1994, 54 (10), PL173-177. 

S. Menzel-Soglowek, Variability of inversion of (R)-Flurbiprofen in different species, J. Pharmaceutical Sciences, 81(No.9) (1992)888. 

Also other members of the profen-family, among them naproxen, flurbiprofen, ketoprofen and tiaprofenic acid, are of great importance today. In general, these are 2-aryl- or 2-heteroaryl-propionic acids, of which in vitro only the (S)-(+)-enantiomer inhibits cyclooxygenase-1 (Fig. 5.84). In vivo, depending on the particular animal species, and also in humans, the (U)-(-)-enantiomer is converted to various degrees into its (S)-enantiomer with the aid of -methylacyl-CoA-racemase, via the Coenzyme A-thioester. In addition, more recent investigations could show that (R)-ibuprofen and (R)-flurbiprofen themselves have also anti-inflammatory properties. Many of the profens, with the exception of naproxen, are therefore marketed as racemates. 

Table I. Experimental data for a-cyclodextrin-iracemic 1-phenylethanol complex (I), 3 Cyclodextrin—S-flurbiprofen complex (II), 3-cyclodextrinr-racemic flurbiprofen complex (III), permethylated a-cyclodextrin—L-mandelic acid complex (IV), permethylated a-cyclodextrinHD-mandelic acid complex (V), permethylated 3-cyclodextrin—R-flurbiprofen complex (VI), and permethylated 3-cyclodextrin—S-flurbiprofen complex (VII)...

The phenyl group is located at the center of the host ring, while the other part of the guest molecule protrudes outward from the 0(2), 0(3) side. The carboxyl group of R-flurbiprofen forms a hydrogen bond with... 

Fig. 8. Permethylated 3-cyclodextrin complexes with R-flurbiprofen (left) and S-flurbiprofen (right).

Fig, 9, Schematic drawings of the crystal packing of permethylated 3-cyclodextrin complexes with R flurbiprofen (left) and S-flurbiprofen (right), Water molecules are shown by full circles. Dotted lines indicate hydrogen bonds. 

S)-Flurbiprofen and (R)-flurbiprofen butyl ester were prepared with >90% ee by a sequential catch/release KR protocol by a serial system of a Upase-filled PBR and an adsorbent-filled catch/release column [105]. 

Rousseau A, Chiap P, Ivanyi R, Crommen J, Fillet M, Servais A-C (2008) Validation of a nonaqueous capillary electrophoretic method for the enantiomeric purity determination of R-flurbiprofen using a single-isomer amino cyclodextrin derivative. J Chromatogr A 1204 219-225... 

Another interesting application of isolated ene reductases is the synthesis of the (R)-enantiomers of the nonsteroidal anti-inflammatory drugs (NSAIDs) belonging to the family of profens (Scheme 3.27). Several methylenic methylesters, such as 93, gave the corresponding (R)-profen precursors (e.g., (R)-94 used for the synthesis of the 3-amyloids reducer (R)-flurbiprofen, see Chapter 13 for further details) [114]. The relevance of these results is increased by the fact that 2-phenylacrylic acid and its esters, in which the methylenic double bond is conjugated to the aromatic ring (as in 93), are usually not accepted by BY and OYEl-3 [115]. 

Figure 13.16 Enzymatic key step in the synthesis of (R)-flurbiprofen methyl ester.

Quarm, E.J., Khwaja, F Zavitz, K.H., and Djakiew, D. (2007) The aryl propionic acid R-flurbiprofen selectively induces p75NTR-dependent decreased survival of prostate tumor cells. Cancer Res., 67, 3254-3262. 

Liu, J., Patel, S, Gillespie, D Whang, K and Couldwell, W. (2012) R-Flurbiprofen, a novel nonsteroidal antiinflammatory drug, decreases cell proliferation and induces apoptosis in pituitary adenoma cells in vitro. J. NeurooncoL, 106, 561-569. 

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