We distinctly remember when this paper came out, and it was not long after that the phrase entered the common lexicon of the medicinal chemists. The study was not that many years after the Rule-of-Five paper, and within our discipline, the naughties become a decade of looking at compounds and defining further guidelines (some becoming un-useful “rules”). This is a must read, as it discuss the key principal of finding the lipophilicity ‘sweet spot’. This is where binding affinity and absorption are sufficient, but not too high, where metabolism and safety concerns arise. The reason for “methyl, ethyl, futile” phrase is simple because it is too easy to increase the lipophilicity of a compound series and “potency” improves, leading to a false sense of progress on a project. Later on came the concept of efficiency in drug design; getting the most out of each atom and lipophilic group. Read the paper and it will improve your thinking in compound design.

Lipophilicity in PK design: methyl, ethyl, futile.   J Comput Aided Mol Des. 2001 Mar;15(3):273-86. 

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