Arhalofenate (MBX 102)
(Synonyms: 芳卤芬酯; MBX 102; JNJ 39659100) 目录号 : GC31462
A prodrug form of a PPARγ partial agonist
Cas No.:24136-23-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Animal experiment: | Male ZDF rats at 8 wk of age are used in the assay. ZDF rats are single housed and allowed access ad libitum to tap water and chow. ZDF rats are screened into three groups with similar mean plasma glucose levels. ZDF rats are cannulated in the jugular vein and the carotid artery and are allowed to recover at least for 2 d. Rats are dosed with either vehicle or Arhalofenate (MBX 102) (100 mg/kg) by oral gavage for 4-7 d. On the day of the clamp experiment, rats are dosed and food is withdrawn 1 h later. After rats are fasted for 4 h, blood samples are taken from the carotid catheter to measure basal glucose and insulin levels. Experiments are initiated with a priming injection (0.5 mL/rat of 5 μCi/mL of d-[3-3H] glucose) and initiation of a constant infusion of d-[3-3H] glucose tracer (8 μCi/mL) at a rate of 10 μL/min for 60 min. After the 1-h tracer-equilibration period, a post-tracer blood sample is collected for glucose, insulin and d-[3-3H] glucose specific activity (SA) measurements. Infusion of tracer glucose is then discontinued, and insulin infusion is initiated (10 μL/min equivalent to 40 mU/kg/min) along with glucose infusion. The glucose infusion rate is adjusted empirically to achieve plasma glucose level at 150 mg/dL ± 5% within the next 1.5-2 h. To facilitate this process, blood samples are collected at 10-min intervals for immediate plasma glucose measurements using a glucometer until the end of the study. Clamp is defined by three consecutive glucose measurements that are within the above defined range. Samples (300-400 μL) at the three time points (10-min interval) are collected for glucose, insulin, and d-[3-3H] glucose SA measurements. |
References: [1]. Gregoire FM, et al. MBX-102/JNJ39659100, a novel peroxisome proliferator-activated receptor-ligand with weak transactivation activity retains antidiabetic properties in the absence of weight gain and edema. Mol Endocrinol. 2009 Jul;23(7):975-88. | |
Arhalofenate is an orally bioavailable prodrug form of the free acid form of a peroxisome proliferator-activated receptor γ (PPARγ) partial agonist.1 It is converted to the active free acid form by nonspecific serum esterases. Arhalofenate has weak PPARγ transactivation activity in a reporter assay but strong transrepression activity, reducing LPS-induced chemokine (C-C motif) ligand 2 (CCL2) secretion in isolated mouse peritoneal macrophages. It reduces fasting plasma glucose levels in ob/ob mouse and Zucker diabetic fatty (ZDF) rat models of type 2 diabetes when administered at doses of 125 and 100 mg/kg, respectively. It also decreases fasting free fatty acid, triglyceride, and cholesterol levels in ZDF rats without increasing body weight when administered at a dose of 100 mg/kg.2 Arhalofenate (250 mg/kg) prevents leukocyte and neutrophil infiltration and IL-1β, IL-6, and chemokine (C-X-C motif) ligand 1 (CXCL1) production in air pouch fluid in a mouse model of gout.3
1.Gregoire, F.M., Zhang, F., Clarke, H.J., et al.MBX-102/JNJ39659100, a novel peroxisome proliferator-activated receptor-ligand with weak transactivation activity retains antidiabetic properties in the absence of weight gain and edemaMol. Endocrinol.23(7)975-988(2009) 2.Chandalia, A., Clarke, H.J., Clemens, L.E., et al.MBX-102/JNJ39659100, a novel non-TZD selective partial PPAR-γ agonist lowers triglyceride independently of PPAR-α activationPPAR Res.706852(2009) 3.McWherter, C., Choi, Y.-J., Serrano, R.L., et al.Arhalofenate acid inhibits monosodium urate crystal-induced inflammatory responses through activation of AMP-activated protein kinase (AMPK) signalingArthritis Res. Ther.20(1)204(2018)
| Cas No. | 24136-23-0 | SDF | |
| 别名 | 芳卤芬酯; MBX 102; JNJ 39659100 | ||
| Canonical SMILES | O=C(OCCNC(C)=O)[C@@H](C1=CC=C(Cl)C=C1)OC2=CC=CC(C(F)(F)F)=C2 | ||
| 分子式 | C19H17ClF3NO4 | 分子量 | 415.79 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4051 mL | 12.0253 mL | 24.0506 mL |
| 5 mM | 0.481 mL | 2.4051 mL | 4.8101 mL |
| 10 mM | 0.2405 mL | 1.2025 mL | 2.4051 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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Arhalofenate acid inhibits monosodium urate crystal-induced inflammatory responses through activation of AMP-activated protein kinase (AMPK) signaling
Arthritis Res Ther.2018 Sep 6;20(1):204.PMID:30189890DOI: 10.1186/s13075-018-1699-4.
Background: Arhalofenate acid, the active acid form of arhalofenate, is a non-agonist peroxisome proliferator-activated receptor γ (PPARγ) ligand, with uricosuric activity via URAT1 inhibition. Phase II studies revealed decreased acute arthritis flares in arhalofenate-treated gout compared with allopurinol alone. Hence, we investigated the anti-inflammatory effects and mechanisms of arhalofenate and its active acid form for responses to monosodium urate (MSU) crystals. Methods: We assessed in-vivo responses to MSU crystals in murine subcutaneous air pouches and in-vitro responses in murine bone marrow-derived macrophages (BMDMs) by enzyme-linked immunosorbent assay (ELISA), SDS-PAGE/Western blot, immunostaining, and transmission electron microscopy analyses. Results: Oral administration of arhalofenate (250 mg/kg) blunted total leukocyte ingress, neutrophil influx, and air pouch fluid interleukin (IL)-1β, IL-6, and CXCL1 in response to MSU crystal injection (p < 0.05 for each). Arhalofenate acid (100 μM) attenuated MSU crystal-induced IL-1β production in BMDMs via inhibition of NLRP3 inflammasome activation. In addition, arhalofenate acid dose-dependently increased activation (as assessed by phosphorylation) of AMP-activated protein kinase (AMPK). Studying AMPKα1 knockout mice, we elucidated that AMPK mediated the anti-inflammatory effects of arhalofenate acid. Moreover, arhalofenate acid attenuated the capacity of MSU crystals to suppress AMPK activity, regulated expression of multiple downstream AMPK targets that modulate mitochondrial function and oxidative stress, preserved intact mitochondrial cristae and volume density, and promoted anti-inflammatory autophagy flux in BMDMs. Conclusions: Arhalofenate acid is anti-inflammatory and acts via AMPK activation and its downstream signaling in macrophages. These effects likely contribute to a reduction of gout flares.
The mechanism of Arhalofenate in alleviating hyperuricemia-Activating PPARγ thereby reducing caspase-1 activity
Drug Dev Res.2020 Nov;81(7):859-866.PMID:32506648DOI: 10.1002/ddr.21699.
Hyperuricemia (HUA) is an important risk factor for renal diseases and contributes to gout. Arhalofenate (Arha) has been proved to have uricosuric activity as an inhibitor of URAT1, organic anion transporter 4 (OAT4) and OAT10. However, the effects of Arha on HUA remain unknown. The objective of this study was to investigate whether Arha could alleviate HUA and uncovered the underlying mechanism in vitro. HK-2 cells were exposed to uric acid (UA) to simulate HUA in vitro. Then cells were treated with Arha, caspase-1 inhibitor Belnacasan (Beln), caspase-11 inhibitor Wedelolactone (Wede) and PPARγ inhibitor Mifobate, respectively. The alteration of cell proliferation, inflammation, pyroptosis and expression of related proteins were detected. Results showed that UA exposure inhibited cell viability and increased IL-1β and IL-18 generation in a concentration dependent manner. Meanwhile, UA activated the cleavage of gasdermin D (GSDMD), enhanced the protein expression of URAT1, OAT4, TLR4, caspase-1, and caspase-11 and reduced PPARγ expression. While the presence of Arha or Beln enhanced cell viability and inhibited cleavage of GSDMD. Wede slightly increased cell viability but failed to prevent GSDMD cleavage. The expression of related proteins except caspase-11was also recovered by Arha. Beln and Wede partially rescued related proteins level except PPARγ compared with model group. Besides, the co-treatment of Mifobate blunted the effects of Arha on cell viability and expression of GSDMD, TLR4, and caspase-1. In conclusion, Arha inhibited UA transport as well as preventing inflammation and pyroptosis via activating PPARγ thereby blocking caspase-1 activation of HUA in vitro.
New urate-lowing therapies
Curr Opin Rheumatol.2018 Mar;30(2):177-182.PMID:29251661DOI: 10.1097/BOR.0000000000000476.
Purpose of review: To discuss recent studies of lesinurad and arhalofenate. Recent findings: Lesinurad acts by blocking urate reabsorption channels URAT-1 and OAT-4. It has urate-lowering effect when used alone and in combination with xanthine oxidase inhibitors (XOIs). Its uricosuric activity depends on glomerular filtration, and its' efficacy is impaired at eGFR less than 30 ml/min. Lesinurad monotherapy (400 mg/day) associates with serum creatinine elevations. However, this risk is substantially attenuated with coprescription of a XOI and when prescribed at a dose of 200 mg/day. Given its' modest urate-lowering effect, and the risk of serum creatinine elevation when used alone, it is licenced for use in combination with XOI for people unable to achieve target serum uric acid with XOI alone. Lesinurad does not have the drug interactions associated with probenecid, however, it is metabolized by CYP2C9, and should be used with caution if CYP2C9 inhibitors are coprescribed. Arhalofenate also acts by blocking URAT-1; however, it also blocks the NALP-3 inflammasome providing gout-specific anti-inflammatory effect. Arhalofenate has a weaker urate-lowering effect than lesinurad and further phase III evaluation is planned. Summary: Lesinurad provides an additional option for people with gout unable to achieve target serum uric acid with XOI alone.
A Randomized, Double-Blind, Active- and Placebo-Controlled Efficacy and Safety Study of Arhalofenate for Reducing Flare in Patients With Gout
Arthritis Rheumatol.2016 Aug;68(8):2027-34.PMID:26989892DOI: 10.1002/art.39684.
Objective: Arhalofenate is a novel antiinflammatory uricosuric agent. The objective of this study was to evaluate its antiflare activity in patients with gout. Methods: This was a 12-week, randomized, double-blind, controlled phase IIb study. Eligible patients had had ≥3 flares of gout during the previous year, had discontinued urate-lowering therapy and colchicine, and had a serum uric acid (UA) level of 7.5-12 mg/dl. Patients were randomly assigned at a 2:2:2:2:1 ratio to receive 600 mg arhalofenate, 800 mg arhalofenate, 300 mg allopurinol, 300 mg allopurinol plus 0.6 mg colchicine, or placebo once a day. The primary outcome measure was the flare incidence (number of flares divided by time of exposure). The serum UA level was a secondary outcome measure. Results: A total of 239 gout patients were randomized and took at least 1 dose of study medication. The primary outcome measure comparing flare incidence between 800 mg arhalofenate and 300 mg allopurinol was achieved, with a 46% decrease in the 800 mg arhalofenate group (0.66 versus 1.24; P = 0.0056). Treatment with 800 mg arhalofenate was also significantly better than placebo (P = 0.049) and not significantly different from treatment with 300 mg allopurinol plus 0.6 mg colchicine (P = 0.091). Mean changes in serum UA level were -12.5% with 600 mg arhalofenate and -16.5% with 800 mg arhalofenate (P = 0.001 and P = 0.0001, respectively, versus -0.9% with placebo). There were no meaningful differences in adverse events (AEs) between groups, and there were no serious AEs related to arhalofenate. Urinary calculus occurred in 1 patient receiving 300 mg allopurinol. No abnormal serum creatinine values >1.5-fold the baseline value were observed in the arhalofenate-treated groups. Conclusion: Arhalofenate at a dosage of 800 mg decreased gout flares significantly compared to allopurinol at a dosage of 300 mg. Arhalofenate was well tolerated and appeared safe. Arhalofenate is the first urate-lowering antiflare therapy.
New medications in development for the treatment of hyperuricemia of gout
Curr Opin Rheumatol.2015 Mar;27(2):164-9.PMID:25603039DOI: 10.1097/BOR.0000000000000146.
Purpose of review: To update recent developments in medications targeting hyperuricemia, but not including medications recently labelled in the European Union and the United States. Recent findings: A new xanthine oxidase inhibitor, Topiloric (Fujiyakuhin Co., Ltd. Japan) Uriadec (Sanwa Kagaku Kenkyusho Co., Ltd. Japan), has been developed and labelled in Japan. An inhibitor of purine nucleoside phosphorylase, Ulodesine, is in development in combination with allopurinol. The rest of the medications in the pipeline for hyperuricemia are targeting renal transporters of uric acid, mainly URAT1 and OAT4, acting as uricosuric agents. Most of them, such as lesinurad and arhalofenate, are being tested in trials in combination with allopurinol and febuxostat. The most potent RDEA3170 is being tested in monotherapy, but also associated with febuxostat. Recently, medications showing dual activity, inhibiting both xanthine oxidoreductase and URAT1, have been communicated or started exploratory clinical trials. There is no report of medications targeting other transporters such as Glut9 or ABCG2. Summary: There are a number of medications in the pipeline targeting hyperuricemia, mostly uricosurics in combination with xanthine oxidase inhibitors, but some targeting both xanthine oxidoreductase and URAT1. Increasing the number of available medications will ensure proper control of hyperuricemia to target serum urate levels in the near future for most, if not all, patients with hyperuricemia.