The lipophilicity mirage: logD as an endpoint in drug discovery

Several metrics and rules such as LLE or Lipinski rules incorporate lipophilicity and are often seen as valid endpoints in drug discovery, which is in fact a Fata Morgana (eng. Mirage). This italian phrase is derived from Latin meaning "fairy", from the belief that these mirages were fairy castles in the air to lure sailors to their death. These mirages distort the object which they are based on significantly, often such that the object is completely unrecognizable [1]. The use of distribution and partition coefficients to explain biological potency ranges back into the first half of the 20th century [2,3,4] and was further developed by Hansch [5]. The octanol water partition coefficient (logDoctanol/water) is defined as the logarithm of the ratio of the concentration of all ionized and un-ionized forms at a specific pH in the two phases. The conceptual simplicity and appealing correlations between logDoctanol/water and e.g. potency and pharmacokinetic parameters has put it in focus for many discussions with tremendous impact in drug discovery.