Ten years have passed since the publication of the ‘rule of five’ physical property guidelines for drug permea- bility 1,2 . The rule of five, which was derived from a database of clinical candidates reaching Phase II trials or further, states that poor absorption or permeability are more likely when cLogP (the calculated 1-octanol–water partition coefficient) is >5; molecular mass is >500 daltons (Da); the number of hydrogen-bond donors (OH plus NH count) is >5; and the number of hydrogen-bond acceptors (O plus N atoms) is >10 (REFS 1,2). Although the rule-of-five properties are interrelated (cLogP actually being a composite property dependent on molecular size, polarity and hydrogen bonding 3 ), its conceptual simplicity and ease of calculation has made it the leading measure of drug-likeness, with the original article having more than 1,500 literature citations. The physicochemical profiles of oral drugs 4–6 are con- sistent with the rule of five, and recent studies on drug absorption have also highlighted the importance of polar surface area (PSA), which is closely correlated to O plus N atom count, and LogD (1-octanol–water coefficient at various pH values) 7,8 . Overall oral bioavailability depends not just on absorption but also on dissolution, gut transit time and first-pass metabolism, so it is perhaps surpris- ing that rat bioavailability can be categorized by simple physical properties such as PSA and rotatable bonds 9,10 , and number of rule-of-five violations, PSA and ioniza- tion state 11 . However, these models do not readily explain human bioavailability data 12 . One further aspect that has received less attention is that bulk molecular properties are relevant to drug safety as well as pharmacokinetics and metabolism: marketed oral drugs, which are rule-of-five compliant 4–6 , have by definition successfully passed rigorous toxicological and clinical safety hurdles. Analyses of drug-likeness inevitably depend on the medicinal chemistry innovation and prevailing strate- gies of the past. However, it is clear that compounds produced by more recent medicinal chemistry efforts do not occupy the same chemical space as historical drugs. From three studies of oral drugs 4–6 , the mean cLogP values were 2.3, 2.5 and 2.5 and mean molecular masses were 333, 337 and 344 Da. By contrast, 1,117 GlaxoSmithKline compounds 9 and 553 Abbott com- pounds 11 that had advanced to pharmacokinetic studies had, respectively, mean cLogP values of 4.3 and 3.9, and molecular mass values of 480 and 434 Da. Additionally, a group of 1,680 optimized compounds from the recent medicinal chemistry literature had a mean cLogP of 4.0 and molecular mass of 435 Da 13 ; and in another literature study, more than 50% of compounds with high potency had cLogP values >4.25 and molecular mass values >425 Da 14 . Drugs and research compounds also differ in physicochemical properties between target protein classes 13,15,16 and therapy areas 17 . Molecular mass and other properties of oral drugs 6,17 , as well as of literature compounds 16 , are also increasing with time. These changes are potentially a concern because physical property inflation may prove detrimental to the health of drug development pipelines. Several studies 4,14,16,18 of compounds in development concur that mean molecular mass declines as compounds progress through Phase I, II and III; moreover, the more AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE15 5RH, UK. Correspondence to P.D.L. e-mail: paul.leeson@astrazeneca.com doi:10.1038/nrd2445 LogP Log of the octanol–water partition coefficient, which is a measure of a drug’s lipophilicity. Defined as the ratio of un-ionized drug distributed between the octanol and water phases at equilibrium. Higher values imply greater lipophilicity. Molecular mass The molecular mass of a substance, frequently called molecular weight, is the mass of one molecule of that substance, and its units are the unified atomic mass unit (u) or Dalton (Da), which equals 1/12 the mass of one atom of carbon-12. Polar surface area (PSA). This is defined as the surface sum over all polar atoms, (usually oxygen and nitrogen), also including attached hydrogens. The influence of drug-like concepts on decision-making in medicinal chemistry Paul D. Leeson and Brian Springthorpe Abstract | The application of guidelines linked to the concept of drug-likeness, such as the ‘rule of five’, has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. The consequences of the marked increase in lipophilicity — the most important drug-like physical property — include a greater likelihood of lack of selectivity and attrition in drug development. Tackling the threat of compound-related toxicological attrition needs to move to the mainstream of medicinal chemistry decision-making. NATURE REVIEWS | DRUG DISCOVERY VOLUME 6 | NOVEMBER 2007 | 881 ANALYSIS © 2007 Nature Publishing Group