Ruling out the rule of five

If you were doing medicinal chemistry after about the year 2000, you definitely got to hear about the ‘rule of five’. Sometimes it was known as the ‘Pfizer rule of five’ or ‘Lipinski’s rule of five’, for the understandable reason that its originator, Chris Lipinski, worked at Pfizer. But it wasn’t just one rule, it was several – and taken together, many people thought that they might tell you how to make drugs that had a better chance of success in clinical trials. 

Drug discovery needs all the help it can get in that department, so it’s no wonder that these ideas got some attention. Failure rates in the clinic are famously around 90%. So what were these rules that offered a way out? Your structure was supposed to have no more than five parts of its structure that were hydrogen bond donors (and no more than 10 that were hydrogen bond acceptors), a molecular weight of no more than 500, and a logP (a measure of a compound’s balance between greasiness and water solubility) of no more than 5. And that was it.