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.[2] As a standalone compound, glutarimide is used in chemical synthesis and research, with no direct therapeutic applications.[3][4]
The drug lenalidomide contains the substructure glutarimide (blue).
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.[2] Its molecular formula, C5H7NO2, 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.[3] It is synthesized by heating glutaric acid with ammonia, followed by dehydration to close the imide ring.[5] N-acyl-glutarimides are key intermediates in N–C(O) cross-coupling reactions due to their destabilized amide bond, enabling applications in organic synthesis.[6]
Pharmacology
Glutarimide itself lacks direct pharmacological activity but is a critical scaffold in several drugs.[2] Derivatives like thalidomide and lenalidomide bind to cereblon (CRBN), an E3 ubiquitin ligase adaptor, promoting protein degradation and exerting immunomodulatory and anti-angiogenic effects.[5] Cycloheximide inhibits protein synthesis by blocking translation elongation in eukaryotic cells, making it a valuable research tool.[3] Glutarimide antibiotics, such as 9-methylstreptimidone, exhibit antiviral, antitumor, and antifungal activities through protein biosynthesis inhibition.[3] The glutarimide moiety’s interaction with biological targets underpins its pharmacological versatility.[5]
Clinical applications
Glutarimide has no therapeutic use alone but is integral to several medications.[2]Lenalidomide, an immunomodulatory drug (IMiD), is approved for multiple myeloma and myelodysplastic syndromes, leveraging CRBN-mediated protein degradation.[5]Thalidomide, initially a sedative, is now used for erythema nodosum leprosum (ENL) and multiple myeloma, despite its teratogenic risks.[5]Glutethimide, a sedative-hypnotic, was prescribed for insomnia but discontinued due to abuse potential.[7]Cycloheximide is used in laboratory research to inhibit protein synthesis but is too toxic for clinical use.[3]
Side effects and toxicity
Glutarimide’s toxicity as a standalone compound is poorly documented, but its derivatives pose significant risks.[5] Thalidomide caused severe birth defects (e.g., phocomelia) in the 1950s, leading to its withdrawal in 1961.[5] Lenalidomide is associated with myelosuppression, thromboembolism, and fatigue, requiring careful monitoring.[5] Glutethimide’s high lipid solubility and variable half-life (5–40 hours) led to overdose risks, respiratory depression, and dependence, prompting its discontinuation.[7] Cycloheximide’s toxicity to eukaryotic cells restricts it to non-clinical applications.[3]
History
Glutarimide was first synthesized in the early 20th century from glutaric acid, initially valued for its synthetic utility.[5] Its pharmacological relevance emerged with thalidomide in the 1950s, marketed as a sedative but withdrawn in 1961 after causing thousands of birth defects.[5] Thalidomide’s reapproval in 1998 for ENL and later for multiple myeloma led to the development of safer IMiDs like lenalidomide.[5] Glutethimide, introduced as a non-barbiturate sedative, was discontinued by 2006 due to abuse and toxicity.[7] Glutarimide remains a key scaffold in modern drug design, particularly for CRBN-targeted therapies.[6]
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