Physicochemical Descriptors

Fairly simple descriptors have been shown to give good correlations to ADME properties. In 1997, Lipinski proposed the 'rule of 5,' an important, but not sufficient filter for oral drugs.22 This 'rule of 5' comprises four rules (molecular weight MW< 500, Clog P < 5, number of hydrogen bond donor atoms HBD < 5, and number of hydrogen bond acceptor atoms HBA< 10) and states that good absorption is less likely for a compound if two or more of these rules are violated. However, this can only help for a first interpretation of a molecule - a compound that fulfills all criteria is more likely to be permeable and, thus, also more likely to be orally bioavailable. Nevertheless, not all compounds that do fulfill the criteria have good bioavailability or even good absorption (e.g., acyclovir, fluvastatin, and terbutaline all have bioavailability below 30%,23 acyclovir also has a fraction absorbed below 30%,24 and they do not violate any of Lipinski's rules). In addition, compounds that do not fulfill the criteria are successfully used as drugs (e.g., cyclosporine or digoxin have both bioavailability up to 60% and thus also reasonable high absorption24). Since the 'rule of 5' is based on the distribution of properties that were calculated for several thousand drugs, such outliers are to be expected. Surprisingly, most of these outliers belong to a few specific compound classes, some of which are known to be substrates to a

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