Gimeracil
[CAS# 103766-25-2]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyridine compound >> Pyridine derivative
• Name: Gimeracil
• Synonyms: Gimestat; 5-Chloropyridine-2,4-diol
• Molecular Formula: C₅H₄ClNO₂
• Molecular Weight: 145.54
• CAS Registry Number: 103766-25-2
• EC Number: 870-589-4
• SMILES: C1=C(C(=CNC1=O)Cl)O

Properties

• Density: 1.6±0.1 g/cm³ Calc.^*
• Boiling point: 524.2±45.0 ºC 760 mmHg (Calc.)^*
• Flash point: 270.8±28.7 ºC (Calc.)^*
• Solubility: DMSO 29 mg/ml (Expl.)
• Index of refraction: 1.641 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P261-P264-P264+P265-P270-P271-P280-P301+P317-P302+P352-P304+P340-P305+P351+P338-P319-P321-P330-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2A	H319
Acute toxicity	Acute Tox.	4	H302

Discovory and Applicatios

Gimeracil, chemically known as 5-chloro-2,4-dihydroxypyridine, is a synthetic compound that emerged from research focused on enhancing the efficacy of anticancer chemotherapeutic agents. Its discovery was primarily driven by efforts to improve the clinical performance of fluoropyrimidine-based drugs, particularly 5-fluorouracil (5-FU), which has been a cornerstone of chemotherapy for various malignancies. During the development of combination therapies, scientists identified that the rapid degradation of 5-FU by the enzyme dihydropyrimidine dehydrogenase (DPD) significantly limited its therapeutic effectiveness. This led to the strategic search for potent DPD inhibitors that could stabilize and prolong the systemic availability of 5-FU without introducing substantial toxicity.

Through extensive screening and optimization studies, gimeracil was identified as a highly potent and selective inhibitor of DPD. Its discovery involved modifications of simple pyridine derivatives, with the inclusion of hydroxyl groups at the 2- and 4-positions and a chlorine atom at the 5-position, yielding a molecule capable of effectively binding to the active site of DPD. Gimeracil demonstrated the ability to markedly inhibit the catabolism of 5-FU, thereby maintaining higher plasma concentrations of the drug for extended periods. This mechanism allowed for improved antitumor efficacy at lower doses of 5-FU, reducing the associated systemic toxicity and enhancing patient tolerability.

The primary application of gimeracil is as a key component of the oral anticancer agent S-1, which is a combination formulation that includes tegafur, gimeracil, and oteracil potassium. Tegafur serves as a prodrug of 5-FU, gradually releasing 5-FU in the body. Gimeracil's role in this combination is to inhibit DPD-mediated degradation of 5-FU, ensuring sustained therapeutic levels. Oteracil potassium is included to reduce gastrointestinal toxicity by inhibiting the phosphorylation of 5-FU specifically in the gut. Together, this combination significantly enhances the pharmacological properties of 5-FU while minimizing its adverse effects, offering a more convenient and effective oral chemotherapy option compared to intravenous 5-FU administration.

Clinical studies have demonstrated that S-1, and thus gimeracil by extension, provides substantial benefits in the treatment of various solid tumors, including gastric, colorectal, pancreatic, and non-small cell lung cancers. The inclusion of gimeracil has been critical in achieving improved response rates and survival outcomes while maintaining a manageable side effect profile. Its ability to modulate 5-FU metabolism represents an important advancement in the rational design of chemotherapeutic regimens.

Beyond its role in S-1, gimeracil has also been studied independently for its pharmacokinetic properties and potential applications. Research has focused on understanding its absorption, distribution, metabolism, and excretion profiles, ensuring its suitability for clinical use. It has been shown that gimeracil is rapidly absorbed after oral administration and exhibits a plasma half-life compatible with the dosing schedules of combination therapies. Importantly, it does not exert significant pharmacological effects by itself at therapeutic concentrations, confirming its primary function as an enzyme inhibitor rather than an active cytotoxic agent.

Overall, the discovery and application of gimeracil represent a significant contribution to the field of oncology. By effectively addressing a major limitation in 5-FU chemotherapy, gimeracil has enabled more efficient and patient-friendly treatment options. Its development exemplifies the importance of enzyme inhibition strategies in improving the therapeutic profiles of established anticancer drugs, and it continues to be an essential component in modern chemotherapeutic regimens.

References

2005. Potassium oxonate, an enzyme inhibitor compounded in S-1, reduces the suppression of antitumor immunity induced by 5-fluorouracil. Cancer Chemotherapy and Pharmacology, 57(5).
DOI: 10.1007/s00280-005-0150-0

2008. Development History and Concept of an Oral Anticancer Agent S-1 (TS-1(R)): Its Clinical Usefulness and Future Vistas. Japanese Journal of Clinical Oncology, 38(11).
DOI: 10.1093/jjco/hyn127

2024. Gemcitabine/gimeracil/oteracil/tegafur. Reactions Weekly, 2085(1).
DOI: 10.1007/s40278-024-70975-6