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Tarenflurbil

Description of tarenflurbil: tarenflurbil is an orally active synthetic enantiomer of flurbiprofen. Tarenflurbil activates c-Jun N terminal kinase, increases AP-1 binding to DNA, and downregulates cyclin D1 expression, resulting in arrest of tumor cells in the G1 phase of the cell cycle and apoptosis. This agent also affects the expression of nuclear factor kappa B, a rapid response transcription factor that stimulates the immune response to tumor cells. Tarenflurbil does not inhibit the enzyme cyclo-oxygenase. Tarenflurbil is currently tested in patients with mild Alzheimer's disease. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   Myriad Genetics, Inc.

Tarenflurbil, or R-flurbiprofen, is the single enantiomer of the racemate NSAID flurbiprofen. For several years, research and trials for the drug were conducted by Myriad Genetics, to investigate its potential as a treatment for Alzheimer's disease; that investigation concluded in June 2008 when the company announced it would discontinue development of the compound.

At proposed therapeutic concentrations, this molecule lacks anti-inflammatory activity, and does not inhibit either cyclooxygenase 1 (COX-1) or cyclooxygenase 2 (COX-2) enzymes. Only the S-enantiomers of arylpropionic acid NSAID can potently inhibit COX, whereas the R-enantiomers exert almost no COX activity. R-Flurbiprofen is inefficiently converted into S-flurbiprofen, with 1.5% of the R-enantiomer undergoing bioinversion to the S-form. Although this compound lacks activity against COX, studies have shown that this drug is a potent reducer of levels of beta amyloid, the main constituent of amyloid plaques in Alzheimer's disease, and therefore there was interest in this drug as a therapeutic agent.

A Phase III clinical study evaluated 800 mg R-flurbiprofen twice-daily versus placebo for 18 months exclusively in 1800 patients with mild Alzheimer's disease. On June 30, 2008, the company announced to discontinued Flurizan due to the disappointed results.  Prior to this termination, Myriad had sold distribution rights in the European Union to Lundbeck for an initial payment of $100 million, which Lundbeck has indicated it will now take as a write-down.  See wikipedia.com

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2: Vellas B. Tarenflurbil for Alzheimer's disease: a "shot on goal" that missed. Lancet Neurol. 2010 Mar;9(3):235-7. PubMed PMID: 20170836.

3: Montine TJ, Larson EB. Late-life dementias: does this unyielding global challenge require a broader view? JAMA. 2009 Dec 16;302(23):2593-4. PubMed PMID: 20009062; PubMed Central PMCID: PMC2827770.

4: Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, Zavitz KH; Tarenflurbil Phase 3 Study Group. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA. 2009 Dec 16;302(23):2557-64. PubMed PMID: 20009055.

5: Andrade C, Radhakrishnan R. The prevention and treatment of cognitive decline and dementia: An overview of recent research on experimental treatments. Indian J Psychiatry. 2009 Jan;51(1):12-25. PubMed PMID: 19742190; PubMed Central PMCID: PMC2738400.

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7: Sabbagh MN. Drug development for Alzheimer's disease: where are we now and where are we headed? Am J Geriatr Pharmacother. 2009 Jun;7(3):167-85. Review. PubMed PMID: 19616185.

8: Imbimbo BP. Why did tarenflurbil fail in Alzheimer's disease? J Alzheimers Dis. 2009;17(4):757-60. PubMed PMID: 19542625.

9: Hendrix SB, Wilcock GK. What we have learned from the Myriad trials. J Nutr Health Aging. 2009 Apr;13(4):362-4. PubMed PMID: 19300881.

10: Williams M. Progress in Alzheimer's disease drug discovery: an update. Curr Opin Investig Drugs. 2009 Jan;10(1):23-34. PubMed PMID: 19127484.

11: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Oct;30(8):643-72. PubMed PMID: 19088949.

12: Zhao X, Rebeck GW, Hoe HS, Andrews PM. Tarenflurbil protection from cytotoxicity is associated with an upregulation of neurotrophins. J Alzheimers Dis. 2008 Nov;15(3):397-407. PubMed PMID: 18997293.

13: Aisen PS. Tarenflurbil: a shot on goal. Lancet Neurol. 2008 Jun;7(6):468-9. Epub 2008 Apr 29. PubMed PMID: 18450518.

14: Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA; Tarenflurbil Phase II Study investigators. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial. Lancet Neurol. 2008 Jun;7(6):483-93. Epub 2008 Apr 29. Erratum in: Lancet Neurol. 2008 Jul;7(7):575. PubMed PMID: 18450517.

15: Galasko DR, Graff-Radford N, May S, Hendrix S, Cottrell BA, Sagi SA, Mather G, Laughlin M, Zavitz KH, Swabb E, Golde TE, Murphy MP, Koo EH. Safety, tolerability, pharmacokinetics, and Abeta levels after short-term administration of R-flurbiprofen in healthy elderly individuals. Alzheimer Dis Assoc Disord. 2007 Oct-Dec;21(4):292-9. PubMed PMID: 18090435.

16: Kukar T, Prescott S, Eriksen JL, Holloway V, Murphy MP, Koo EH, Golde TE, Nicolle MM. Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci. 2007 Jul 24;8:54. PubMed PMID: 17650315; PubMed Central PMCID: PMC1948891.

17: Christensen DD. Changing the course of Alzheimer's disease: anti-amyloid disease-modifying treatments on the horizon. Prim Care Companion J Clin Psychiatry. 2007;9(1):32-41. PubMed PMID: 17599166; PubMed Central PMCID: PMC1894844.

18: Christensen DD. Alzheimer's disease: progress in the development of anti-amyloid disease-modifying therapies. CNS Spectr. 2007 Feb;12(2):113-6, 119-23. Review. PubMed PMID: 17277711.

19: Molecule of the month. MPC-7869 (Flurizan). Drug News Perspect. 2005 Mar;18(2):141. PubMed PMID: 15883622.