What else could be at number 5? In this article, the authors consider the properties that influence the solubility and permeability of drugs. This was partly a response to the introduction of high-throughput screening to drug discovery which yielded compounds that had never been tested in cells or in vivo and consequently had properties that need not be consistent with good solubility and permeability. They showed that there had been an increase in higher molecular weight compounds and an increase in logP of compounds in the previous decade. The properties of a set of over 2000 drugs were considered (with a selection criteria for clinical exposure likely to favour orally bioavailable drugs). Of these, about 10% was found to have a clogP above 5, about 11% a molecular weight above 500; such compounds are likely to have poor solubility. A crude estimate of the number of hydrogen bond donors (number of OH + number of NH) and even cruder estimate of the number of acceptors (number of O + number of N) were also examined; only 8% of the drugs have donor count above 5 and only 12 % an acceptor count above 10. These latter groups likely suffer from poor permeability. The period since this paper has seen a host of attempts to derive “rules” for other types of compounds (fragments, leads etc) although more nuanced views have also emerged. Personally, we think that the prompt to consider the importance of solubility and permeability was a good one but the introduction of the idea of “rules” about what a drug looks like was a misstep.
“Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings” by Lipinski, Lombardo, Dominy and Feeney.
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