Title:Prodrug Strategies for Critical Drug Developability Issues: Part I
Volume: 21
Issue: 24
Author(s): Xingyue Ji
Affiliation:
Abstract: Drug development is a very time, capital, and labor-intensive process. It was anticipated that bringing a novel chemical entity
to market would take over a billion dollars and around 14 years [1]. In addition, drug development is characterized by a
very high attrition rate both in preclinical and clinical studies. It was reported that only 40% of drug candidates with the most
drug-like properties could make their way into clinical trials, and only 10% of these can eventually reach FDA approval [2].
After analyzing the data from seven UK‐based pharmaceutical companies from 1964 through 1985, Prentis et al. found that
39% of failure was attributed to poor pharmacokinetic (PK) profiles in humans, 29% was attributed to a lack of clinical efficacy,
21% was attributed to toxicity and adverse effects, and about 6% was attributed to commercial limitations [3]. When a
drug candidate is identified with one of these issues (except the commercial limitations), normally, a new round of structureactivity
or structure-property relationship (SAR/SPR) studies is carried out to generate a new chemical entity with improved
profiles, and in most cases, such a process is time and labor-intensive. Alternatively, prodrug strategy can be leveraged to efficiently
address associated drug developability issues without making enormous derivatives. Prodrug strategy has been demonstrated
to be very successful and fruitful in drug development, with around 20% of approved drugs from 2008 through 2020
being clarified as prodrugs [4]. In recent years, prodrug strategy has also been leveraged to address the delivery issues associated
with gasotransmitters, including NO, H2S, CO as well as SO2 [5-8]. In this thematic issue, six excellent reviews were
included, focusing on varied prodrug strategies in addressing different drug developability issues associated with anticancer
drugs, central nervous system (CNS) drugs, and gasotransmitters....
