Wrestling with Lipinski's rule of 5

Picture of multiple round pills with the number five on them.

Source: Chemical & Engineering News

You need to know the rules to break them. More eloquent versions of this adage have been attributed to visionaries as varied as Pablo Picasso and the Dalai Lama. But is an adage that works for famous artists and spiritual leaders holding medicinal chemists back? For more than 25 years, scientists have been grappling with Lipinski’s rule of 5, which is four guidelines based on multiples of five (hence the name). It was devised to help chemists design drugs that can be taken orally—the largest category of medicines.

For a medicine to be successful when it’s swallowed, it must dissolve in the stomach’s acidic environment and traverse the cell membrane in the gut. In 1997, Christopher A. Lipinski and colleagues working at the pharmaceutical giant Pfizer published guidelines on how to make compounds that can do just that by striking a balance between solubility and permeability (Adv. Drug Delivery Rev., DOI: 10.1016/S0169-409X(96)00423-1). Since its publication, the paper introducing Lipinski’s rule of 5 has been cited more than 24,000 times, according to Google Scholar, and has been republished twice. It has become both dogmatic and divisive.

The rules in retrospect

Hartung and colleagues recently published a perspective about the rule of 5 called “Rules Were Made to Be Broken” (Nat. Rev. Chem. 2023, DOI: 10.1038/s41570-022-00451-0). To write it, he collected input from chemists on Twitter. “I would say there are 10 times more people out there who believe that the rule of 5 does not help drug discovery chemists than the number of people who think that this is a good thing,” he says. “Most are concerned that it limits the creativity of chemists.”

But there are those who don’t think we should disregard the rules entirely. Mary Mader, vice president of molecular innovation at Indiana Biosciences Research Institute, says most chemists think of the rule of 5 as guardrails rather than rules. Designing an orally bioavailable drug is complicated, she says.

“To try to reduce it to only a handful of properties is pretty simplistic, and yet it still is useful,” she says. “The sweet spot for any chemical series will differ by the scaffold you’re working on. And yet there is a generally true phenomenon that if you want the properties of solubility, absorption, and metabolic stability, you’re often still working in that space” defined by the rule of 5.

To read the full article, go to Chemical & Engineering News.