4-Phenylbutyric acid

Absorption

Following oral administration of a single 5g dose of sodium phenylbutyrate, the Cmax was 195-218 μg/mL under fasting conditions and the Tmax was one hour. The effect of food on drug absorption is unknown.

Toxicity

In animals, lethality was seen at a dose of 1586 mg/kg sodium phenylbutyrate; however, this is a supra-therapeutic dose and acute toxicity is unlikely. No adverse experiences have been reported involving overdoses of sodium phenylbutyrate in patients with urea cycle disorders. High levels of phenylacetate, the active metabolite of phenylbutyric acid, can cause nausea, headache, emesis, fatigue, weakness, lethargy, somnolence, dizziness, slurred speech, memory loss, confusion, and disorientation.
In the event of an overdose, discontinue the drug and institute supportive measures. Hemodialysis or peritoneal dialysis may be beneficial. Animal studies in the scientific literature have demonstrated the embryo-fetal toxicity potential of phenylacetate, the major metabolite of phenylbutyrate.

Chemical properties

4-Phenylbutyric acid is white to slightly yellowish crystalline powder. It is slightly soluble in chloroform and methanol. Its solubility in water is 5.3 g/l (at 40 °C).

The Uses of 4-Phenylbutyric acid

4-Phenylbutyric acid is used as a chemical chaperone involved in protein-folding disorders. It is involved in the synthesis of dyes and an active pharmaceutical ingredient intermediate.

Indications

Phenylbutyric acid is used for the treatment of various conditions, including urea cycle disorders, neonatal-onset deficiency, late-onset deficiency disease in patients with a history of hyperammonemic encephalopathy. Phenylbutyric acid must be combined with dietary protein restriction and, in some cases, essential amino acid supplementation.
Phenylbutyric acid, as sodium phenylbutyrate, is used in combination with tauroursodeoxycholic acid to treat amyotrophic lateral sclerosis (ALS) in adults.

Background

Phenylbutyric acid is a fatty acid and a derivative of butyric acid naturally produced by colonic bacteria fermentation. It demonstrates a number of cellular and biological effects, such as relieving inflammation and acting as a chemical chaperone. It is used to treat genetic metabolic syndromes, neuropathies, and urea cycle disorders.

What are the applications of Application

4-Phenylbutyric acid is a chemical chaperone that suppresses oxidative stress

Definition

4-Phenylbutyric acid is a monocarboxylic acid the structure of which is that of butyric acid substituted with a phenyl group at C-4. It is a histone deacetylase inhibitor that displays anticancer activity. It inhibits cell proliferation, invasion and migration and induces apopto is in glioma cells. It also inhibits protein isoprenylation, depletes plasma glutamine, increases production of foetal haemoglobin through transcriptional activation of the gamma-globin gene and affects hPPARgamma activation.

Preparation

4-phenylbutyric acid is obtained by the reaction of benzene with butyrolactone in the presence of aluminum chloride, followed by neutralization with base.
Synthesis of 4-phenylbutyric acid

What are the applications of Application

4-Phenylbutyric acid (4-PBA) is used in the treatment of urea cycle disorders under the trade name Buphenyl. 4-PBA has been used as a selective inhibitor of endoplasmic reticulum stress (ERS).
4-Phenylbutyric acid is used as organic intermediates. It can also be used as a reactant in the synthesis of:
1-Tetralone using Lewis acid catalyst.
4,N-diphenylbutyramide.

Synthesis Reference(s)

Tetrahedron Letters, 32, p. 3309, 1991 DOI: 10.1016/S0040-4039(00)92693-5

General Description

4-Phenylbutyric acid (4-PBA) is a small-molecular-weight fatty acid with a terminal aromatic group, and its sodium salt (sodium 4-phenyl butyrate) has been used for the treatment of urea cycle disorders. This molecule is also used for the treatment of sickle cell diseases and thalassemia owing to its ability to activate β-globin transcription. Moreover, 4-PBA is employed as an orally bioavailable agent for the treatment of spinal muscular atrophy (SMA) and tumors.
Neuroprotective Effects of 4-phenylbutyric Acid and Its Derivatives: Possible Therapeutics for Neurodegenerative Diseases

Pharmacokinetics

Phenylbutyric acid decreases elevated plasma ammonia glutamine levels in patients with urea cycle disorders. It increases waste nitrogen excretion in the form of phenylacetylglutamine.
In the intestines, phenylbutyric acid was shown to reduce mucosal inflammation, regulate transepithelial fluid transport, and improve oxidative status. Some studies report antineoplastic properties of phenylbutyric acid, showing that phenylbutyric acid can promote growth arrest and apoptosis of cancer cells. It is suggested that phenylbutyric acid can act as an ammonia scavenger, chemical chaperone, and histone deacetylase inhibitor.

Metabolism

The major sites for metabolism of sodium phenylbutyrate are the liver and kidney. Phenylbutyric acid is rapidly metabolized to phenylacetate via beta-oxidation. Phenylacetate is conjugated with phenylacetyl-CoA, which in turn combines with glutamine via acetylation to form phenylacetylglutamine.

Purification Methods

Crystallise the acid from pet ether (b 40-60o). [Beilstein 9 IV 1811.]