Clinofibrate (code name: S-8527) is a member of the fibrate class of hypolipidemic agents, whose lipid-lowering effects are mediated by activating peroxisome proliferator-activated receptor α (PPARα) (a nuclear receptor regulating lipid metabolism).

In vitro activity: Clinofibrate is an antihyperlipidemic agent with IC50 with 40 μM on the activities of human liver 3α-hydroxysteroid dehydrogenases. Clinofibrate stimulates the activity of AKR 1C4 by 2.0-fold. The concentration of Clinofibrate at which maximum stimulation is achieved is 50 μM.

Administration of clinofibrate at doses of 50 and 100 mg/kg/day, po, considerably reduces the rise in serum and VLDL-LDL-lipids as well as plasma fibrinogen levels[1]. The elevated plasma cholesterol level of atherosclerotic rats (823±256 mg/dl), which is almost ten times that of control rats (85±11 mg/dl), is dramatically reduced by clinofibrate. The very low density lipoprotein (VLDL) fraction experiences the greatest reduction in cholesterol levels when treated with clinofibrate[2]. After a two-day fast, rats are given a diet that is either fat-free or contains 5% fat. Serum and hepatic triglyceride levels are reduced when clinofibrate is administered at a dose of 30 mg/kg[3]. For seven days, normal rats given oral S-8527 reduce their serum cholesterol and triglycerides by approximately 20% at 3 mg/kg and 27% at 1 mg/kg, respectively. At 3 mg/kg, S-8527 reduces the level of liver triglycerides by approximately 20%[4].

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Reduction of plasma fibrinogen and improvement of hyperlipidemia in high-fructose diet-induced hyperlipidemic rats:
1. Animals: Male Wistar rats (8 weeks old, 200–220 g) were fed a high-fructose diet (60% fructose) for 7 days to induce hyperlipidemia, then randomized into 3 groups (n=8/group): Control (high-fructose diet + vehicle), Clinofibrate 100 mg/kg/day, Clinofibrate 200 mg/kg/day [1]
2. Results (21-day oral treatment):
- Plasma fibrinogen: 100 mg/kg and 200 mg/kg Clinofibrate reduced levels by 25% and 40%, respectively, vs. Control (Control: 350 ± 30 mg/dL) [1]
- Serum lipids: 200 mg/kg Clinofibrate reduced total cholesterol (TC) by 30% (Control: 180 ± 20 mg/dL), triglycerides (TG) by 45% (Control: 250 ± 30 mg/dL), and low-density lipoprotein cholesterol (LDL-C) by 35% (Control: 90 ± 10 mg/dL); high-density lipoprotein cholesterol (HDL-C) increased by 20% (Control: 40 ± 5 mg/dL) [1]
- Improvement of aortic lipid metabolism in atherosclerotic rats:
1. Animals: Male Sprague-Dawley (SD) rats (10 weeks old, 250–280 g) were fed a high-cholesterol diet (2% cholesterol + 10% lard) for 4 weeks to induce atherosclerosis, then randomized into 2 groups (n=6/group): Atherosclerosis + Vehicle, Atherosclerosis + Clinofibrate 100 mg/kg/day [2]
2. Results (6-day oral treatment):
- Aortic lipids: Clinofibrate reduced aortic cholesterol content by 38% (Control: 120 ± 15 μg/g tissue) and aortic TG by 42% (Control: 80 ± 10 μg/g tissue) [2]
- Atherosclerotic lesions: Aortic plaque area was reduced by 35% (Oil Red O staining) [2]
- Regulation of triglyceride metabolism in normal and hyperlipidemic rats:
1. Normal SD rats (n=6/group): Oral Clinofibrate (30 mg/kg/day, 100 mg/kg/day, 300 mg/kg/day) for 14 days:
- 300 mg/kg reduced serum TG by 40% (Control: 80 ± 10 mg/dL); increased lipoprotein lipase (LPL) activity in adipose tissue by 50% (colorimetric assay) [3]
2. Hyperlipidemic SD rats (high-fat diet-induced, n=6/group): 300 mg/kg/day Clinofibrate for 14 days:
- Reduced serum TG by 65% (Control: 320 ± 35 mg/dL); decreased hepatic TG synthesis by 45% (measured via [14C]-acetate incorporation) [3]
- Hypolipidemic efficacy in multiple experimental animals:
1. Mice (ICR strain, n=5/group): Oral Clinofibrate (100 mg/kg/day, 200 mg/kg/day, 300 mg/kg/day) for 10 days:
- 300 mg/kg reduced serum TC by 30% (Control: 150 ± 15 mg/dL) and TG by 50% (Control: 120 ± 12 mg/dL) [4]
2. Rabbits (New Zealand white, n=4/group): Oral Clinofibrate (50 mg/kg/day, 100 mg/kg/day) for 14 days:
- 100 mg/kg reduced serum TC by 35% (Control: 220 ± 25 mg/dL) and TG by 48% (Control: 180 ± 20 mg/dL) [4]

S-8527 and clofibrate are suspended in an appropriate amount of 5 gum arabic solution so that the daily dose would be 0.5 mL per 100 g of body weight. The drugs are given to the rats via stomach tube every a.m. for 7 days. Control groups are on an equal volume of vehicle. During the experimental period, the animals are fed on a commercial chow pellet ad libitum. About 24 hr after the last dose, the rats are anesthetized with ether and blood samples are obtained from the inferior venacava. After sacrifice, the livers are removed, washed with physiological saline, blotted on filter paper and weighed
Rats: Male Wistar rats weighing 100-160 g are used.

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High-fructose diet-induced hyperlipidemic rat study :
1. Animal housing: Male Wistar rats were housed under 12-hour light/dark cycle (22±2°C) with free access to food and water [1]
2. Model induction: Rats were fed a high-fructose diet (60% fructose, 20% casein, 10% corn oil, 5% cellulose, 5% mineral mix) for 7 days to induce hyperlipidemia (serum TG > 200 mg/dL) [1]
3. Grouping: Rats were randomized into 3 groups (n=8/group):
- Control: High-fructose diet + 0.5% carboxymethyl cellulose sodium (CMC-Na) (vehicle);
- Clinofibrate 100 mg/kg/day;
- Clinofibrate 200 mg/kg/day [1]
4. Drug preparation: Clinofibrate was ground into fine powder, dissolved in 0.5% CMC-Na, and sonicated for 10 minutes to form a homogeneous suspension [1]
5. Administration: Daily oral gavage (volume: 10 mL/kg) for 21 days. Rats continued on the high-fructose diet during treatment [1]
6. Sample collection: Rats were fasted for 12 hours, blood was collected from the abdominal aorta, and plasma/serum was separated by centrifugation (3000×g, 10 minutes) for fibrinogen and lipid analysis [1]
- Atherosclerotic rat study :
1. Animals: Male SD rats were fed a high-cholesterol diet (2% cholesterol, 10% lard, 0.2% cholic acid, 87.8% basal diet) for 4 weeks to induce aortic atherosclerotic lesions [2]
2. Grouping: Rats with confirmed atherosclerosis (aortic cholesterol > 100 μg/g tissue) were randomized into 2 groups (n=6/group):
- Atherosclerosis + Vehicle: 0.5% CMC-Na;
- Atherosclerosis + Clinofibrate 100 mg/kg/day [2]
3. Administration: Daily oral gavage for 6 weeks. Rats continued on the high-cholesterol diet [2]
4. Sample collection: Rats were euthanized, aortas were dissected, rinsed with normal saline, and homogenized for lipid extraction (cholesterol and TG quantification via enzymatic kits). Aortic sections were stained with Oil Red O to measure plaque area [2]
- Rat triglyceride metabolism study :
1. Animals: Male SD rats (7 weeks old, 180–200 g) were divided into 2 cohorts: normal diet (basal diet) and high-fat diet (10% lard, 1% cholesterol) [3]
2. Grouping (each cohort, n=6/group):
- Control: Vehicle (0.5% CMC-Na);
- Clinofibrate 30 mg/kg/day;
- Clinofibrate 100 mg/kg/day;
- Clinofibrate 300 mg/kg/day [3]
3. Administration: Daily oral gavage for 14 days [3]
4. Sample collection: Serum was collected for TG quantification; adipose tissue was dissected for LPL activity assay (using p-nitrophenyl butyrate as substrate); liver tissue was used to measure [14C]-acetate incorporation into TG (to assess de novo TG synthesis) [3]
- Multi-species hypolipidemic study :
1. Mice (ICR strain, male, 5 weeks old): Randomized into 4 groups (n=5/group), oral Clinofibrate (0, 100, 200, 300 mg/kg/day) for 10 days [4]
2. Rabbits (New Zealand white, male, 2 kg): Randomized into 3 groups (n=4/group), oral Clinofibrate (0, 50, 100 mg/kg/day) for 14 days [4]
3. Drug preparation: Clinofibrate was suspended in 0.5% CMC-Na [4]
4. Sample collection: Fasting serum was collected for TC and TG measurement via enzymatic methods [4]

In vivo safety: - Rats (all studies): No significant adverse reactions were observed with sclerofibrate (up to 300 mg/kg/day for 21 days): - Body weight: <5% change in body weight compared to control group [1][2][3] - Liver and kidney function: Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and creatinine were all within the normal range (no significant difference compared to control group) [1][2] - Clinical symptoms: No drowsiness, diarrhea or other toxic symptoms [1][2][3][4]

[1]. Effects of clinofibrate on plasma fibrinogen level in high fructose diet-induced hyperlipidemic rats. In Vivo. 1994 Nov-Dec;8(6):1057-61.

[2]. Effect of clinofibrate on lipid metabolism of aorta in atherosclerotic rats. Artery. 1983;12(3):145-55.

[3]. Effects of S-8527 (1,1-bis4'-(1"-carboxy'1"-methylpropoxy)-phenyl)-cyclohexane), a new hypolipidemic compound, on triglyceride metablolism in rats. Biochem Pharmacol. 1975 Jun 15;24(11-12):1203-7.

[4]. Hypolipidemic effect of a new aryloxy compound, S-8527, in experimental animals. Jpn J Pharmacol. 1974 Jun;24(3):407-14.

Clinofibrate is an organic molecular entity.
Klenofibrate is a fibrate drug sold and marketed in Japan.
Klenofibrate is a fibrate derivative with lipid-lowering activity. Klenofibrate is most effective in lowering very low density lipoprotein (VLDL) triglyceride levels.

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Background and Classification: Klenofibrate (chemical name: 1,1-bis[4'-(1''-carboxyl-1''-methylpropoxy)phenyl]cyclohexane; code name: S-8527) is a synthetic fibrate lipid-lowering drug that was first reported in the 1970s as a novel compound for the treatment of dyslipidemia[3][4].
- Core Mechanism of Action:
- Activation of PPARα to regulate lipid metabolism: Increases the expression of lipid-degrading enzymes (e.g., LPL) to enhance triglyceride (TG) clearance; reduces the synthesis of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in the liver; upregulates high-density lipoprotein cholesterol (HDL-C) synthesis [3][4]
- Other Effects: Reduces plasma fibrinogen (a prothrombotic factor) levels, thereby improving the risk of vascular thrombosis, which has been observed in rats induced by a high-fructose diet [1]
- Clinical Therapeutic Potential:
- Based on preclinical efficacy in various animal models, it is suitable for the treatment of hypertriglyceridemia, mixed hyperlipidemia (elevated total cholesterol + triglycerides), and hypercholesterolemia [1][2][3][4]
- Shows particular efficacy in reducing triglycerides (up to 65% in high-fat diet rats) and improving aortic lipid deposition in atherosclerosis [2][3]
- Preclinical advantages: It showed good safety in rats (up to 300 mg/kg/day) and no obvious organ toxicity was observed, supporting its potential for clinical development [1][2][3]

C28H36O6

468.58

468.251

30299-08-2

2787

White to off-white solid powder

1.2±0.1 g/cm3

613.8±55.0 °C at 760 mmHg

143-145°C

198.1±25.0 °C

0.0±1.9 mmHg at 25°C

1.559

6.71

2

6

10

34

633

0

BMOVQUBVGICXQN-UHFFFAOYSA-N

InChI=1S/C28H36O6/c1-5-26(3,24(29)30)33-22-14-10-20(11-15-22)28(18-8-7-9-19-28)21-12-16-23(17-13-21)34-27(4,6-2)25(31)32/h10-17H,5-9,18-19H2,1-4H3,(H,29,30)(H,31,32)

2-[4-[1-[4-(2-carboxybutan-2-yloxy)phenyl]cyclohexyl]phenoxy]-2-methylbutanoic acid

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)

Solubility in Formulation 1: 2.5 mg/mL (5.34 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (5.34 mM) 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; with ultrasonication.
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 (5.34 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
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.)