Successes, failures, and future prospects of prodrugs and their clinical impact

ABSTRACT

Introduction: Ample efforts have been carried out to improve the efficacy of a variety of drugs. The prodrugs approach was found to be a safe haven for providing medications with improved pharmacokinetic and pharmacodynamic properties.

Areas covered: Herein, several selected successful prodrugs are reported and categorized. These include prodrugs for the treatment of the cardiovascular system, the central nervous system, the gastrointestinal tract, ophthalmology, the immune system, and oncology. In addition, some successful antiviral, antibacterial, antifungal, antiprotozoal, and several other miscellaneous prodrugs are documented. Further, a number of failed prodrugs are reported followed by those potentially promising prodrugs of the future.

Expert opinion: The molecular revolution and accumulation of knowledge on the chemistry of enzymes and transporters has opened the door widely to novel successful prodrugs. For example, newer platelet aggregation inhibitors could signal the end of the warfarin era with their demanding treatment follow-up. The discovery of prodrugs can significantly improve the quality of patient care. Future attention should be focused towards directed enzyme prodrug therapy (DEPT). This strategy employs the design of artificial enzymes to activate prodrugs at specific sites. Agents designed for use in DEPT medicine can be directed at antibodies, genes, viruses, and clostridia.

KEYWORDS:

• ACE inhibitors
• aldoxorubicin
• ARB
• baloxavir marboxil
• clinical
• dabigatran etexilate
• evofosfamide
• failure
• fosnetupitant
• latanoprostene bunod
• pomaglumetad methionil
• prodrug
• sofosbuvir
• success

Article highlights

• Prodrug strategies were implemented to improve the overall efficacy of therapies for numerous indications.

• These strategies have proven to be successful in numerous aspects of pharmacology and can directly affect disease management.

• The molecular revolution and accumulation of knowledge on the chemistry of enzymes and transporters has opened the door widely to novel successful prodrugs.

• Utilizing computational methods such as ab initio, DFT, semi-empirical and molecular mechanics methods along with x-ray and spectroscopic data of enzymes and transporter are crucially needed for designing effective prodrugs that lead to drugs with high bioavailability.

• The prodrug strategy, while impactful has not always been successful with some having been withdrawn from the market,

• Future attention should be paid towards directed enzyme prodrug therapy (DEPT). This strategy employs the design of artificial enzymes to activate prodrugs at specific sites.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.