Chirally Pure Non-Steroidal Anti-Inflammatory Drugs

Home , Chiral switch, Dexibuprofen, Dexketoprofen

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Introduction Joy Philip, Trivandrum Chirality is defined as the geometric property of a rigid object (like a molecule or drug) of not being super imposable with its mirror image. Chirality is a property of matter found throughout Dexketoprofen S(+)Ketoprofen] biological systems, from the basic building blocks of life such Trometamol as amino acids, carbohydrates, and lipids to the layout of the Racemic Ketoprofen is a 50:50 mixture of S(+)- and R(-)- human body. The two mirror images of a chiral molecule are enantiomers7. Most or all COX inhibitory activity of Ketoprofen termed R and S enantiomers. Both enantiomers have the same is attributed to the S(+)-enantiomer (Dexketoprofen)8. The chemical composition and structure, but in chiral environments R-enantiomer is 30 to 5000 times less potent as an inhibitor such as the receptors and enzymes in the body, they can behave of COX-1 and about 100 times less potent as an inhibitor of differently. A racemate or a racemic mixture is a mixture COX-29. In addition, S-Ketoprofen less GI ulcerogenic potential as containing equal amounts of both enantiomers. In case of a compared to the racemic Ketoprofen. In fact, R-enantiomer may drug, the two enantiomers may have different pharmacokinetic contribute to the pathogenesis of intestinal ulcers10. and pharmacodynamic properties. It is worth remembering the following important comments in the European Journal Of Clinical The absorption of S-enantiomer from racemic Ketoprofen and Pharmacology, 1984, 26, 663-8 : “Too often, and even without Dexketoprofen trometamol has been found to be equivalent and 11 it being noticed, data in the scientific literature on mixture of rapid . The fast absorption could account for the suitability of stereoisomers, racemates, are presented as if only one compound Dexketoprofen in the management of acute pain. Dexketoprofen 9,12 were involved.T he neglect of stereochemical aspects of drug action is effective at half the dose of racemate . Several clinical trials …. degrades many pharmacokinetic studies to expensive “highly conducted with orally administered Dexketoprofen trometamol in sophisticated pseudoscientific nonsense…..The development of acute painful inflammatory conditions- dental pain, dysmenorrhea, ‘hybrid’ drugs, presented as a step forward in medicinal chemistry, acute musculoskeletal injuries, renal colic, orthopedic surgeries- tends to be step backward in therapy.” Clearly, 50% impurity in and chronic painful inflammatory conditions like osteoarthritis, pharmaceuticals is not acceptable. have confirmed its high analgesic potency and good tolerability profile13-26. When compared to enantiomerically equivalent Chirality and NSAIDs doses of Ketoprofen, Dexketoprofen trometamol has shown a comparable analgesic efficacy and tolerability13,16,17,19-21 but a The NSAIDs have been intensively studied from the perspective faster onset of action13,16. In addition, Dexketoprofen improves of stereoselectivity. For NSAIDs, it is the enantiomer possessing the activity of opioid analgesics like Fentanyl35 and reduces the the S configuration that almost exclusively possess the anti- opioid requirement24. inflammatory/ analgesic activity while R enantiomers lacks such 1 2-6 activity and may have some different activity . For example, Salient features of Dexketoprofen R-Flurbiprofen and R-Etodolac are undergoing development for the potential treatment of Alzheimer’s disease2 and cancer3-6, • Most or all COX inhibitory activity of Ketoprofen is attrib- respectively. However, most of the NSAIDs are traditionally uted to the S(+)-enantiomer (Dexketoprofen) administered as racemates except Naproxen which is available • R-enantiomer is 30 to 5000 times less potent as an inhibitor as the single S enantiomer. In the following sections, new unichiral of COX-1 and about 100 times less potent as an inhibitor of NSAIDs- Dexketoprofen, Dexibuprofen and S-Etodolac- are COX-2 discussed. • Dexketoprofen is less ulcerogenic than the racemic Keto- profen and R-Ketoprofen Medicine Update 2010  Vol. 20

• Dexketoprofen has faster absorption than racemate shown better gastrointestinal tolerability when compared with non-selective NSAIDs51. Etodolac possesses a more favorable • Dexketoprofen has established efficacy and tolerability in therapeutic index between anti-inflammatory effects and gastric the treatment of acute and chronic painful conditions irritation as compared to other NSAIDs52,53. However, it is • Dexketoprofen has comparable analgesic efficacy and toler- the S-enantiomer of Etodolac that possesses almost all of the ability but a faster onset of action than Ketoprofen anti-inflammatory activity while R-Etodolac is almost inactive. S-Etodolac is 2.6 times more potent than the racemate and 100 Dexibuprofen [S(+)Ibuprofen] times more potent than R-enantiomer54. Furthermore, S-Etodolac achieves greater concentrations in synovial fluid than plasma Racemic Ibuprofen contains equal quantities of R(-)Ibuprofen compared to R-Etodolac55. S-Etodolac rapidly attains the peak and S(+)Ibuprofen. R-Ibuprofen and Dexibuprofen differ in their plasma concentration and is rapidly cleared from plasma compared physicochemical, pharmacological and metabolic properties. to R-Etodolac. R- and S-Etodolac competitively interact with each S-Ibuprofen or Dexibuprofen is the pharmacologically active other for binding to human serum albumin and are displaced by enantiomer of racemic Ibuprofen. Dexibuprofen is the S(+) each other56. In an open label, multicentric, comparative clinical (dextrorotatory)-enantiomer of Ibuprofen and accounts for trial in 108 Indian patients with osteoarthritis, it was found that virtually all pharmacodynamic (analgesic, anti-inflammatory, 27,28 S-Etodolac extended release 300 mg tablet was equally effective antipyretic) activities of the racemic compound . In vitro, in improving pain, stiffness and physical function when compared Dexibuprofen is over 100 times as potent as the R-enantiomer 57 27 to Etodolac extended release 600 mg tablet . Both the drugs as an inhibitor of prostaglandin biosynthesis . In therapy, potential were very well tolerated in this study. Thus, it is justified to use advantages of Dexibuprofen over racemic Ibuprofen include a single active, potent enantiomer with the anti-inflammatory lesser toxicity, greater clinical efficacy and/or less variability in activity i.e. S-Etodolac. therapeutic effects achieved, and easier dose optimization, all at half the dose of Ibuprofen. Several clinical trials and post marketing Salient features of S-Etodolac surveillance studies have been performed to elucidate the efficacy and safety of Dexibuprofen29-33. The findings from these studies • S-enantiomer of Etodolac possesses almost all of the anti- demonstrate that Dexibuprofen is effective and very well tolerated inflammatory activity while R-Etodolac is almost inactive 29 in patients with acute dental pain and chronic osteoarthritis • S-Etodolac is 2.6 times more potent than the racemate and 30 pain . These effects are comparable to Diclofenac, Celecoxib and 100 times more potent than R-enantiomer enantiomerically equivalent dose of racemic Ibuprofen29-33. • S-Etodolac achieves greater concentrations in synovial fluid Salient features of Dexibuprofen than plasma • Dexibuprofen is the pharmacologically active enantiomer of • S-Etodolac has a favorable pharmacokinetic profile com- racemic Ibuprofen pared to R-Etodolac. • Dexibuprofen is over 100 times as potent as the R-enantio- • Efficacy and tolerability of S-Etodolac is comparable to the mer racemate

• Dexibuprofen has lesser toxicity, greater clinical efficacy, Conclusion less variability in therapeutic effects achieved and easier dose optimization, all at half the dose of Ibuprofen The NSAIDs used in clinical practice contain both R and S enantiomers, which have different pharmacological properties. • Dexibuprofen is effective and very well tolerated in patients Since, it is the S-enantiomer that has the anti-inflammatory/ with osteoarthritis and dental pain analgesic activity while R-enantiomer lacks such activity, it is thus • Efficacy comparable to Diclofenac, Celecoxib and double imperative to perform the chiral switch i.e. to develop only the dose of racemic Ibuprofen therapeutically effective S-enantiomer. This avoids the use of 50% impurity in the form of R-enantiomer and thus provides a less S(+)Etodolac complex pharmacokinetics, avoids the enantiomer interactions and reduces the metabolic load on the body. The development of S-Etodolac is a chirally pure, pharmacologically active form of Dexketoprofen, Dexibuprofen and S-Etodolac is certainly a step Etodolac containing only S(+)enantiomer. The racemate Etodolac forward in this direction. has analgesic, antipyretic, and anti-inflammatory properties34 with more selectivity for induced COX-2 (associated with References inflammation) over COX-1 (cytoprotective)35. Numerous studies have established the efficacy and tolerability of racemic Etodolac 1. lópez-Muñoz FJ, Ventura R, Díaz MI, Hernández GP, Domínguez AM, García ML, et al- Analysis of antinociceptive effects of flurbiprofen en- compared to other NSAIDs in the treatment of osteoarthritis, antiomers in a rat model of arthritic pain. Methods Find Exp Clin Phar- rheumatoid arthritis and post-operative pain34,36-50. Etodolac has macol. 2000 Oct;22(8):641-5.

838 Chirally Pure Non-Steroidal Anti-Inflammatory Drugs

2. Geerts H- Drug evaluation: (R)-flurbiprofen--an enantiomer of - flur Ketoprofen in the treatment of primary dysmenorrhea. J Clin Pharma- biprofen for the treatment of Alzheimer’s disease. IDrugs. 2007 col 1998; 38:65S-73S. Feb;10(2):121-33. 21. data on File 2- A Multicentric, Comparative, Randomized, Parallel 3. lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM, et al- Activation Group Clinical Trial to Evaluate the Efficacy and Safety of Dexketopro- of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc fen trometamol in the Treatment of Dysmenorrhea. Natl Acad Sci U S A. 2004;101:3118-3123. 22. leman P, Kapadia Y, Herington J- Randomised controlled trial of the 4. hedvat M, Jain A, Carson DA, Leoni LM, Huang G, Holden S, et al- Inhi- onset of analgesic efficacy of dexketoprofen and Diclofenac in lower bition of HER-kinase activation prevents ERK-mediated degradation of limb injury. Emerg Med J. 2003 Nov;20(6):511-3. PPARgamma. Cancer Cell. 2004; 5:565-574. 23. gaitán G, Herrero JF- Subeffective doses of dexketoprofen trometamol 5. Kolluri SK, Corr M, James SY, Bernasconi M, Lu D, Liu W, et al- The R- enhance the potency and duration of fentanyl antinociception. Br J enantiomer of the nonsteroidal antiinflammatory drug etodolac binds Pharmacol. 2002 Jan;135(2):393-8. retinoid X receptor and induces tumor-selective apoptosis. Proc Natl 24. iohom G, Walsh M, Higgins G, Shorten G- Effect of perioperative ad- Acad Sci U S A. 2005;102:2525-2530. ministration of dexketoprofen on opioid requirements and inflamma- 6. yasui H, Hideshima T, Hamasaki M, Roccaro AM, Shiraishi N, Kumar S, et tory response following elective hip arthroplasty.Br J Anaesth. 2002 al- SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, over- Apr;88(4):520-6. comes drug resistance, and enhances the activity of dexamethasone in 25. miranda HF, Puig MM, Dursteler C, Prieto JC, Pinardi G- Dexketoprofen- multiple myeloma. 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