In the last few years, many detailed statistical analyses have been reported aiming to have a detailed understanding of the molecular-level properties that are important for optimal oral bioavailability. Lipinski and colleagues (1997) introduced the so-called "rule of 5," which states that poor absorption or permeations more likely when the MW is over 500; the log P is over 5; the hydrogen-bond donors are more than 5; and the hydrogen-bond acceptors are more than 10.
More recently, Veber et al. (2002) found polar surface area and molecular flexibility to be important predictors of good oral bioavailability, interestingly independent of MW. After analyzing the oral bioavailability results measured in rats for over 1,100 drug candidates studied at SmithKline Beecham, they found an unexpected positive influence of increasing molecular rigidity as measured by the number of rotatable bonds and the expected negative impact of increasing polar surface area. Figure 2.1 shows the fraction of compounds with an oral bioavailability of 20% or greater as a function of MW and rotatable bond count. It is clear that the effect of molecular rigidity on oral bioavailability is rather independent of MW.
Given that the major contributors to the polar surface area are hydrogen-bond donors or acceptors and also the rotatable bond count in general increases with MW, these findings are still consistent with the rule of 5. However, these results do suggest that candidate design directed at reduced flexibility and polar surface area without having to reduce MW could still be successful in achieving a high oral bioavailability.
Since expectations for drug candidates tailored for the pharmacological targets have changed significantly over the years, do the necessary characteristics for oral delivery also change? Several statistical analyses of over 1,000 marketed drugs indicate that lower MW, balanced log P, and greater rigidity remain important features of oral drug molecules (Wenlock et al., 2003). When the physicochemi-cal properties of oral drugs in different phases of clinical development are compared to those already marketed (Fig. 2.2), it is interesting that the mean MW of orally administered drugs in development decreases in later phases and gradually converges toward the mean MW of marketed oral drugs. It is clear that the most lipophilic compounds get discontinued from development, suggesting that physicochemical properties are intimately linked to physiological control.
To ensure that these drug-like properties are part of the drug design, approaches to address drug "developability" have been emphasized over the last decade (Kerns and Di, 2003; Huang and Tong, 2004; Borchardt et al., 2006). The empirical rules such as the rule of 5 are now widely applied by many pharmaceutical companies as an alert system for compounds with potential solubility and permeability problems. Since lead optimization often leads to further increases in molecular size and structural complexity, controlling molecular properties within the drug-like domain while optimizing binding efficiency with good selectivity for the desired target remain a major challenge to drug design.
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