Introduction
Prodrugs are medications that, once administered, are metabolized in the body to release the active ingredient. They help to improve a medication’s effectiveness and can in some cases avoid certain side effects or toxicities. The main purpose for designing a prodrug is to overcome issues related to the physicochemical properties of the drug, including solubility, absorption, distribution, and instability. In a recent example, scientists in the Syngene SynVent™ platform for integrated therapeutic discovery leveraged a prodrug strategy to overcome the low solubility of a drug intended for the treatment of status epilepticus, a critical neurological condition characterized by recurrent epileptic seizures.
Desired Characteristics of the Prodrug
The parent compound, currently in Phase 3 clinical development for epilepsy as an oral treatment, is unsuitable for intravenous (IV) injection due to its very low solubility in aqueous media. To overcome this solubility limitation, a prodrug has been developed. The key characteristics of an ideal prodrug include:
- Sufficient solubility in IV formulation (5mg/mL)
- Chemical stability in IV formulation
- Conversion to the parent drug in humans without precipitation
- High in vivo conversion efficiency from prodrug to the parent drug in animals
Challenges in Solubility
The parent compound exhibited low solubility, and developing a salt for this molecule to improve aqueous solubility was not feasible. To address this, Syngene aimed to develop a chemically stable prodrug with enhanced aqueous solubility across different pH levels, ensuring rapid conversion to the parent compound post-IV administration.
Syngene’s Approach
The SynVent scientists integrated medicinal chemistry and ADME (Absorption, Distribution, Metabolism, and Excretion) experiments to solve this challenge, applying a highly efficient screening approach to identify the best prodrugs candidates to advance to in vivo pharmacokinetic (PK) studies.
Scientists evaluated various prodrug candidates using in vitro assays, for solubility, chemical and metabolic stability. The top-performing prodrugs were chosen for animal testing (in vivo PK studies) to investigate how the whole body converts the prodrug into an active drug. Before final selection, the most promising candidates were tested for long-term stability in solution (liquid form) and solid-state (powder or tablet form).
Achieved outcome
- Based on medicinal chemistry optimization studies, scientists identified a series of prodrugs containing a phosphate group that significantly improved the parent compound’s solubility. The solubility experienced an over 2,500-fold enhancement, meeting the project’s objective.
- The prodrug incorporates a cleavable linker and solubilizing group, ensuring that the linker group is rapidly cleaved in vivo.
- Producing different phosphate salts is essential, as it plays a key role in determining the solid-state properties and stability of the resulting compounds. Various phosphate salts were synthesized using ion-exchange resin technology, showcasing excellent purity.
Conclusion
By leveraging the SynVent Integrated Drug Discovery platform, Syngene scientists successfully developed highly soluble and stable prodrugs to overcome key challenges in IV drug formulation. Notably, this research introduces a new option for treating epilepsy through an IV formulation. The prodrug rapidly breaks down inside the body to release the parent drug, ensuring efficient delivery and therapeutic effect. This represents a significant advancement in improving drug efficacy and patient outcomes.
References
- Stella, V.J., Charman, W.N.A. & Naringrekar, V.H. Prodrugs. Drugs 29, 455–473 (1985). https://doi.org/10.2165/00003495- 198529050-00002
- Kurian R, Wang H. Prodrugs in Oncology: Bioactivation and Impact on Therapeutic Efficacy and Toxicity. International Journal of Molecular Sciences. 2025; 26(3):988. https://doi.org/10.3390/ijms26030988
- Status Epilepticus: What It Is, Causes, Symptoms & Treatment