Veber 2002: molecular properties that influence the oral bioavailability of drug candidates
An analysis of over a thousand experimental drug candidates that found molecules with few rotatable bonds and a modest polar surface area were far more likely to be absorbed when swallowed, giving medicinal chemists two simple rules that shaped the design of oral cancer drugs.
Overview
Veber and colleagues at GlaxoSmithKline analysed rat oral bioavailability data for about 1,100 drug candidates and related it to calculated molecular properties. Compounds with ten or fewer rotatable bonds and a polar surface area of 140 square angstroms or less (or twelve or fewer hydrogen bond donors and acceptors) had a high probability of good oral bioavailability, largely independent of molecular weight, which had been the emphasis of earlier rules. The paper argued that reduced molecular flexibility and polar surface area, not size alone, are what predict oral absorption.
- Analysis of oral bioavailability in rats for about 1,100 drug candidates.
- Ten or fewer rotatable bonds and polar surface area of 140 square angstroms or less predicted good oral bioavailability.
- Molecular weight was a weaker predictor than flexibility and polarity.
Veber's rules, alongside Lipinski's rule of five, are used across the industry to decide whether a molecule can become a pill. They set the boundaries within which most oral kinase inhibitors and other targeted cancer drugs were designed, and the current push into larger molecules such as PROTACs and macrocycles is partly an effort to work beyond them.
- Based on rat data from one company's compounds.
- Later oral drugs, including many beyond these limits, show the rules are guides rather than laws.