Fenofibrate

Chemical Properties

Crystalline Solid

Originator

Lipantyl,Fournier,France,1975

Uses

Antilipemic. It is a lipid regulating drug. Increases high density lipoprotein levels by reducing cholesteryl ester transfer protein expresion.

Uses

antihyperlipidemic

Uses

Cardiovascular disease

Uses

Fenofibrate has been used:

• to study its effect on plasma lipids, liver phenotype and gene expression
• to study its impact on endothelium-dependent vasodilatation of thoracic aorta
• to administer to NASH knock-in mice along with a high fat diet (HFD) to study its effect

Definition

ChEBI: A chlorobenzophenone that is (4-chlorophenyl)(phenyl)methanone substituted by a [2-methyl-1-oxo-1-(propan-2-yloxy)propan-2-yl]oxy group at position 1 on the phenyl ring.

Manufacturing Process

(a) Preparation of p-(4-chlorobenzoyl)-phenoxyisobutyric acid: 1 mol of 4- hydroxy-4'-chlorobenzophenone is dissolved in anhydrous acetone and then 5 mols of powdered sodium hydroxide is added. The corresponding sodium phenoxide precipitates. Refluxing is effected, and then, 1.5 mols of CHCl3 diluted with anhydrous acetone is added and the resulting mixture is refluxed for 10 hours. After cooling, water is added, the acetone is evaporated, the aqueous phase is washed with ether and acidified and the organic phase is redissolved in ether and extracted into a solution of bicarbonate. The bicarbonate solution is than acidified to obtain the desired acid, having a melting point of 185°C, with a yield of 75%.
(b) Preparation of fenofibrate: 1 mol of the acid obtained is converted into its acid chloride using thionyl chloride (2.5 mols). 1 mol of the acid chloride is then condensed with 1.05 mol of isopropyl alcohol in the presence of 0.98 mol of pyridine in an inert solvent such as benzene.
Since traces of SO2 (which has a bad smell) may be obtained from the thionyl chloride, it is preferable to avoid this disadvantage by carrying out the esterification directly.

Therapeutic Function

Antihyperlipoproteinemic

General Description

Fenofibrate, 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid 1-methylethyl ester (Tricor),has structural features represented in clofibrate. The primarydifference involves the second aromatic ring. This imparts agreater lipophilic character than exists in clofibrate, resultingin a much more potent hypocholesterolemic and triglycerideloweringagent. Also, this structural modification results in alower dose requirement than with clofibrate or gemfibrozil.

Biochem/physiol Actions

Fenofibrate increases high density lipoprotein levels by reducing cholesteryl ester transfer protein expression. It is used in treating the condition of increased cholesterol levels in the blood, abnormal lipid levels in the body and also hypertriglyceridaemia. Fenofibrate is a lipid regulating drug and proliferator-activated receptor-α (PPARα) mediates its action. It decreases the plasma levels of fibrinogen and C-reactive protein. By this fenofibrate allows better flow-mediated dilatation and reduces the risk of atherosclerosis. Fenofibrate is also known to reduce uric acid levels.

Synthesis

New synthetic plan for fenofibrate via lithium-based flash chemistry: starting from 4-bromophenol or 4-iodophenol, the aryl halide substrates isopropyl 2-(4-bromophenoxy)-2-methyl propanoate (1) or isopropyl 2-(4-iodophenoxy)-2-methyl propanoate (5) were first prepared on a gram scale; a fast Li-halogen exchange with the sterically hindered lithium reagent MesLi at −50 °C then generated the short-lived ArLi intermediate 2 bearing an aliphatic ester (n-BuLi, sec-BuLi, and PhLi performed poorly owing to their nucleophilic attack on the ester group); this intermediate was sequentially coupled with the electrophile 4-chlorobenzoyl chloride in a 3D-printed static mixer reactor (SMR, R2, Ø 500 µm, L 1.0 cm, connected with capillary reactors R1 and R3 at both ends) to directly afford the diaryl-ketone product fenofibrate in a single flow step, with the best yield of 76% under the optimal conditions of 5 equivalents of 4-chlorobenzoyl chloride in CH₂Cl₂ at a flow rate of 3 mL min−1 [1].

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: increased risk of myopathy with daptomycin - try to avoid concomitant use.
Anticoagulants: enhances effect of coumarins and phenindione; dose of anticoagulant should be reduced by up to 50% and readjusted by monitoring INR.
Antidiabetics: may improve glucose tolerance and have an additive effect with insulin or sulphonylureas.
Ciclosporin: ciclosporin levels appear to be unaffected; however, it is recommended that concomitant therapy should be avoided because of the possibility of elevated serum creatinine levels.
Colchicine: possible increased risk of myopathy.
Lipid-regulating drugs: increased risk of myopathy in combination with statins and ezetimibe (maximum 20 mg of rosuvastatin); increased risk of cholelithiasis and gallbladder disease with ezetimibe - avoid with ezetimibe.

Metabolism

After oral administration, fenofibrate is rapidly hydrolysed by esterases to the active metabolite fenofibric acid.
No unchanged fenofibrate can be detected in the plasma. Fenofibric acid is excreted mainly in the urine, mainly as the glucuronide conjugate, but also as a reduced form of fenofibric acid and its glucuronide; practically all the drug is eliminated from the body within 6 days

storage

Store at RT

References

[1] Kawale, S. A., Kang, D.-C., Ahn, G.-N., Mottafegh, A., Kang, J.-H., Na, G.-S., Kim, D.-P. (2023). Rapid flow synthesis of fenofibrate via scalable flash chemistry with in-line Li recovery. Chemical Engineering Journal, 477, 147033. https://doi.org/10.1016/j.cej.2023.147033