As of 2022, the average time to bring a potential Drug candidate through drug development to reach the market is approximately 14 years. The entire research and regulatory process, estimated to cost USD $2 billion, spans drug discovery, preclinical testing, clinical trials, regulatory applications, and post-marketing surveillance. Although the latter stages of this pipeline are more well-known, sponsor companies and contract research organizations (CROs) do not underestimate the importance of the first step: drug discovery. Among one of the most foundational concepts in drug design is the ‘rule of five’ (Ro5), also known as Lipinski’s rule of 5, which was introduced in 1997. Read on to learn how these rules have shifted the drug discovery process over the last few decades.

Lipinski’s Rule of Five

Recognizing common characteristics associated with 90% of effective oral drugs which have reached phase II clinical testing, Christopher Lipinski, a researcher for Pfizer at the time, released guidelines known as the Ro5. These rules were intended to better assess whether a potential compound has the right physical properties, all represented as multiples of five, to be pharmacologically active in the human body.

Lipinski’s rule states that an orally active drug must meet at least three of the following criteria:

1. Molecular mass less than 500 Daltons
2. No more than 5 bonds between hydrogen atoms and either nitrogen or oxygen atoms (hydrogen bond donors)
3. No more than a total of 10 nitrogen or oxygen atoms (hydrogen bond acceptors)
4. A clogP, a measure of how soluble a compound is in water compared with oil, of less than 5

When taken together, these rules help evaluate a compound’s drug-likeness to determine whether they are small and lipophilic enough to be absorbed across cell membranes, but hydrophilic enough to dissolve in the stomach.

The Impact on Lead Generation

With rapid advances in combinatorial chemistry occurring in the 1990s, scientists were equipped with tools to quickly create large libraries of synthetic compounds for high throughput screening. Prior to the Ro5, there was a high volume of compound generation to increase the chances of finding a promising lead. When Lipinski’s Ro5 was first published, it was intended to help researchers conduct the discovery process with more focus and efficiency. For example, there was little point in developing a drug molecule that would be too large to even make it through the intestinal lining. Interestingly, these rules eventually became a central dogma in medicinal chemistry because they provided useful boundaries for drug design, which helped speed up the discovery process.

Prior to Lipinski’s research, drug discovery and drug development were not considered to have much overlap by large pharmaceutical sponsors like Pfizer at the time. In fact, many potential molecular entities would move into development and then remain stuck there, likely because their physicochemical properties were not ideal. Therefore, introducing the Ro5 marked a turning point in the pharmaceutical industry for raising the standard of lead compound quality. This way, if a newly found drug failed to meet one or more criteria, then chemists would have a clearer idea of what challenges to expect during testing.

Knowing When to Break the Rules

It’s important to understand Lipinski’s original intention when sharing the Ro5; it was never meant to be a one-size-fits-all approach to drug design, but that is how it was seen for many years. If a molecule did not fit the criteria, it would often be flagged or discarded. However, later research by other pharmaceutical companies found that excluding these molecules was throwing away opportunities to find promising leads. In 2017, AbbVie created its own library of compounds that failed to adhere to the Ro5, named “beyond the rule of 5” (bRo5). They found that many bRo5 drugs had been successfully tested against immunosuppression (e.g. cyclosporine A), viral or infectious diseases (e.g. HIV protease inhibitors), oncology (e.g. taxanes), and cardiology (e.g. digoxin). Findings such as this have caused some scientists to reassess whether the Ro5 provides more limitations than guidance in drug discovery.

Moving Beyond the Rule of Five

Like any other rule-of-thumb, there will always be exceptions. Lipinski’s Ro5 ushered in a new era of property-based drug design and aimed to help make drug discovery more efficient. However, as our understanding of science and technology grows, every sponsor’s or CRO’s R&D team must recognize that there are opportunities to find novel drugs beyond these rules, as well as within them. Although the Ro5 should not be disregarded entirely, there are enough successful bRo5 drugs on the market to demonstrate that there is plenty of room for creativity and rule-bending in drug design.

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