Glutarimide, also known as piperidine-2,6-dione, is an organic compound with the chemical formula C5H7NO2. It is a white crystalline powder formed by the dehydration of the amide of glutaric acid. Glutarimide serves as a core structural component in several pharmacologically active compounds, including thalidomide, lenalidomide, cycloheximide, and glutethimide, which exhibit immunomodulatory, anticancer, or antibiotic properties.
Chemical properties
Glutarimide is a heterocyclic compound with a six-membered piperidine ring containing two ketone groups at positions 2 and 6, forming a dicarboximide structure.
Its molecular formula, C
5H
7NO
2, corresponds to a molecular weight of 113.114 g/mol, with a melting point of 152–154 °C and solubility in water, ethanol, and acetone.
It is synthesized by heating glutaric acid with ammonia, followed by dehydration to close the imide ring.
N-acyl-glutarimides are key intermediates in N–C(O) cross-coupling reactions due to their destabilized amide bond, enabling applications in organic synthesis.
Pharmacology
Glutarimide itself lacks direct pharmacological activity but is a critical scaffold in several drugs.
Derivatives like thalidomide and lenalidomide bind to cereblon (CRBN), an E3 ubiquitin ligase adaptor, promoting protein degradation and exerting immunomodulatory and anti-angiogenic effects.
Cycloheximide inhibits protein synthesis by blocking translation elongation in eukaryotic cells, making it a valuable research tool.
Glutarimide antibiotics, such as 9-methylstreptimidone, exhibit antiviral, antitumor, and antifungal activities through protein biosynthesis inhibition.
The glutarimide moiety’s interaction with biological targets underpins its pharmacological versatility.
Clinical applications
Glutarimide has no therapeutic use alone but is integral to several medications.
, an immunomodulatory drug (IMiD), is approved for multiple myeloma and myelodysplastic syndromes, leveraging CRBN-mediated protein degradation.
, initially a sedative, is now used for erythema nodosum leprosum (ENL) and multiple myeloma, despite its teratogenic risks.
, a sedative-hypnotic, was prescribed for insomnia but discontinued due to abuse potential.
is used in laboratory research to inhibit protein synthesis but is too toxic for clinical use.
Side effects and toxicity
Glutarimide’s toxicity as a standalone compound is poorly documented, but its derivatives pose significant risks.
Thalidomide caused severe birth defects (e.g., phocomelia) in the 1950s, leading to its withdrawal in 1961.
Lenalidomide is associated with myelosuppression, thromboembolism, and fatigue, requiring careful monitoring.
Glutethimide’s high lipid solubility and variable half-life (5–40 hours) led to overdose risks, respiratory depression, and dependence, prompting its discontinuation.
Cycloheximide’s toxicity to eukaryotic cells restricts it to non-clinical applications.
History
Glutarimide was first synthesized in the early 20th century from glutaric acid, initially valued for its synthetic utility.
Its pharmacological relevance emerged with thalidomide in the 1950s, marketed as a sedative but withdrawn in 1961 after causing thousands of birth defects.
Thalidomide’s reapproval in 1998 for ENL and later for multiple myeloma led to the development of safer IMiDs like lenalidomide.
Glutethimide, introduced as a non-barbiturate sedative, was discontinued by 2006 due to abuse and toxicity.
Glutarimide remains a key scaffold in modern drug design, particularly for CRBN-targeted therapies.
See also
