(R)-Flurbiprofen, or tartenflurbil, has the ability to dramatically lower Aβ release while simultaneously raising intracellular Aβ levels. Both 9-cis-RA and unlabeled (R)-flurbiprofen competitively block the interaction of [3H]9-cis-RA with RXRα. (9-cis-retinoid acid, or 9-cis-RA) inhibits Tarenflurbil ((R)-Flurbiprofen)'s lowering of Aβ secretion, and (R)-Flurbiprofen can interfere with the interaction between RXRα and 9-cis-RA). The intracellular Aβ species levels are markedly increased upon treatment with tartenflurbil ((R)-Flurbiprofen)[1]. It is evident that second generation GSMs and nonsteroidal anti-inflammatory drug-based GSMs have different mechanisms of action with regard to Notch processing because Tarenflurbil ((R) )-Flurbiprofen, a well-known nonsteroidal anti-inflammatory drug, affects only Aβ and does not affect Notch β formation[2].

In C57BL6/J mice that develop a non-remitting form of the disease and in SJL mice that develop a relapsing-remitting (RR)-EAE, the effects of both an early and late start of treatment with Tarenflurbil ((R)-Flurbiprofen) are evaluated. When administered within three days of immunization, tartenflurbil ((R)-Flurbiprofen) totally prevents the development of clinical EAE scores in C57BL6/J mice. We call this regimen "preventive treatment." Since the effect is dose-dependent, 5 mg/kg/day is the minimal daily dose required for full prevention. The positive control, Fingolimod (FTY720, 0.5 mg/kg/day), has effects similar to those of Tarenflurbil ((R)-Flurbiprofen). In C57BL6/J mice, tareflurbil ((R)-Flurbiprofen) also significantly lowers clinical EAE scores when treatment is started just prior to the onset of clinical manifestations, a strategy known as semi-therapeutic (10 mg/kg/day), and when treatment is started on day 13 (5 mg/g/day), after the disease has fully developed[3].

Multiple detailed in vivo protocols were used to evaluate the effects of Tarenflurbil in EAE models.

1. **Animals:** Female C57BL6/J mice (for primary progressive EAE) and female SJL mice (for relapsing-remitting EAE), aged 10-12 weeks at immunization, were used. [3]
2. **Drug Formulation and Administration:** Tarenflurbil was administered orally via the drinking water at doses of 2.5, 5, or 10 mg/kg/day. For late-therapeutic treatment in severely affected C57BL6/J mice, it was administered via drug-soaked sweet cornflakes to ensure intake. FTY720 (fingolimod, 0.5 mg/kg/day) was used as a positive control. [3]
3. **EAE Induction:**
- **C57BL6/J:** Mice were immunized subcutaneously with 200 μg MOG35-55 peptide emulsified in Complete Freund's Adjuvant (CFA), followed by two intraperitoneal (i.p.) injections of 200 ng pertussis toxin (PTX) at 1-2 h and 24 h post-immunization. [3]
- **SJL:** Mice were immunized subcutaneously with 200 μg PLP139-151 peptide in CFA, followed by two i.p. injections of 200 ng PTX. [3]
4. **Treatment Regimens:**
- **Preventive:** Started 3 days after immunization. [3]
- **Semi-therapeutic:** Started 7-8 days after immunization (before symptom onset). [3]
- **Late-therapeutic:** Started after full disease development (day 13 for C57BL6/J; day 19 during first remission for SJL). For late treatment, mice were allocated as score-matched pairs. [3]
5. **Bone Marrow Transplantation (BMX):** Recipient C57BL6/J mice were irradiated (9.5 Gy) and received an i.v. injection of 6 × 10⁶ bone marrow cells from β-actin-EGFP donor mice. EAE was induced 3 weeks after transplantation. [3]
6. **Clinical Scoring and Behavioral Tests:** EAE scores were assessed daily. Rotarod performance and nociceptive behavior (hot plate, Hargreaves, dynamic plantar, acetone, tail flick tests) were evaluated at various time points. [3]
7. **In Vivo Imaging:** Mice were anesthetized with isoflurane and imaged using an IVIS Lumina Spectrum. Probes used: Xenolight RediJect Inflammation Probe (i.p., for MPO activity), MMPsense-680 (i.v., for metalloproteinase activity), BSA-Cy5.5 (i.v., for blood-brain barrier leakage), and DBT (i.v., for myelin imaging). [3]
8. **Tissue Collection and Ex Vivo Analysis:** At defined time points, mice were perfused, and tissues (spinal cord, brain, spleen, optic nerve) were collected for immunofluorescence, FACS analysis, LC-MS/MS (endocannabinoids, prostaglandins, flurbiprofen enantiomers), ELISA (MBP), and microarray gene expression analysis. [3]

Metabolism / Metabolites
The known human metabolites of flurbiprofen include (2S,3S,4S,5R)-6-[(2R)-2-(3-fluoro-4-phenylphenyl)propionyl]oxy-3,4,5-trihydroxyoxacyclohexane-2-carboxylic acid.

[1]. Retinoid X receptor-alpha mediates (R )-flurbiprofen's effect on the levels of Alzheimer's beta-amyloid. J Neurochem. 2009 Oct;111(1):142-9.

[2]. Second generation γ-secretase modulators exhibit different modulation of Notch β and Aβ production. J Biol Chem. 2012 Sep 21;287(39):32640-50.

[3]. R-flurbiprofen attenuates experimental autoimmune encephalomyelitis in mice. EMBO Mol Med. 2014 Sep 30;6(11):1398-422.

(R)-Flurbiprofen is a flurbiprofen, and it is the enantiomer of (S)-flurbiprofen. Tarenflurbil is an investigational drug that was previously used to treat patients with mild Alzheimer's disease. It is a selective amyloid depressant (SALA) that reduces the levels of the toxic peptide β-amyloid 42 (Aβ42) in cultured human cells and animal models. Aβ42 is a major initiator of neurotoxicity and amyloid plaque formation in the brains of Alzheimer's patients. Development of this drug for the treatment of Alzheimer's disease was terminated in June 2008. Tarenflurbil was also used in clinical trials for the treatment of prostate cancer. Tarenflurbil is the oral active synthetic enantiomer of flurbiprofen. Tarenflurbil activates c-Jun N-terminal kinase, increases AP-1 binding to DNA, and downregulates the expression of cyclin D1, thereby causing tumor cells to arrest in the G1 phase of the cell cycle and undergo apoptosis. This drug also affects the expression of nuclear factor κB, a fast-response transcription factor that stimulates the body's immune response to tumor cells. R-flurbiprofen does not inhibit cyclooxygenase.

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Drug Indications
Its application/treatment in Alzheimer's disease and prostate cancer is under investigation.

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Mechanism of Action
MPC-7869 is not an inhibitor of cyclooxygenases (COX-1 and COX-2). This compound regulates signal transduction and transcriptional activation pathways associated with nuclear factor κB (NF-κB), a major transcription factor involved in the expression of various molecules, including cell growth, cell death, and inflammation. Furthermore, MPC-7869 has recently been shown to regulate γ-secretase activity and selectively reduce Aβ42 peptide levels in vitro and in vivo, thereby reducing amyloid pathology in the brain. MPC-7869 has a good safety profile and has demonstrated high efficacy in animal models of cancer and Alzheimer's disease. In transgenic mouse studies, MPC-7869 reduced amyloid levels in the brain and prevented memory loss.

C15H13FO2

244.26

244.089

51543-40-9

Flurbiprofen;5104-49-4

92337

White to off-white solid powder

1.2±0.1 g/cm3

376.2±30.0 °C at 760 mmHg

110-113ºC

181.3±24.6 °C

0.0±0.9 mmHg at 25°C

1.568

4.11

1

3

3

18

286

1

C[C@H](C1=CC(=C(C=C1)C2=CC=CC=C2)F)C(=O)O

SYTBZMRGLBWNTM-SNVBAGLBSA-N

InChI=1S/C15H13FO2/c1-10(15(17)18)12-7-8-13(14(16)9-12)11-5-3-2-4-6-11/h2-10H,1H3,(H,17,18)/t10-/m1/s1

(2R)-2-(3-fluoro-4-phenylphenyl)propanoic acid

(R)-Flurbiprofen; E 7869; MPC 7869; E-7869; MPC7869; E7869; Flurizan; Furbiprofen; MPC-7869;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 50 mg/mL (~204.70 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.23 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (10.23 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (10.23 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)