Membrane Penetration Including Lipinski Rule of Five

In drug discovery projects, an issue of major importance is the design of drug molecules capable of penetrating different biological membranes effectively and rapidly enough to allow effective concentrations to build up at the therapeutic target. The structure and physiochemical properties of the drug molecule obviously are of decisive importance, and it is possible to establish the following empirical rules:

• Some small and rather water soluble substances pass in and out of cells through water lined transmembrane pores.

• Other polar agents are conducted into or out of cells by membrane associated and energy-consuming proteins. Polar nutrients that the cell requires, such as glucose and many amino acids, fit into this category. More recently, drug resistance by cells has been shown to be mediated in many cases by analogous protein im- and exporters.

• The blood-brain barrier (BBB) normally is not easily permeable by neutral amino acids. However, such compounds with sufficiently small difference between the pKa values will have a relatively low I/U ratio indicating the ratio between ionized (zwitterionic) and unionized molecules in solution. As an example, THIP (Figure I.4) has pKa values of 4.4 and 8.5 and a calculated I/U ratio of about 1000. Thus, 0.1% of THIP in solution is unionized, and this fraction permits THIP to penetrate the BBB very easily. Other neutral amino acids typically have I/U ratios around 500,000 and thus very low fractions of unionized molecules in solution, and such compounds normally do not penetrate into the brain after systemic administration.

• Molecules that are partially water soluble and partially lipid soluble can pass through cell membranes by passive diffusion and are driven in the direction of the lowest concentration.

• In cells lining the intestinal tract, it is possible for molecules with these characteristics to pass into the body through the cell membrane alone.

• Finally, it is also possible for molecules with suitable water solubility, small size, and compact shape to pass into the body between cells. This last route is generally not available for passage into the CNS, because the cells are pressed closely together and thus closing off these functions to form the BBB.

Whereas there are no guarantees and many exceptions, the majority of effective oral drugs obey the Lipinski rule of five:

• The substance should have a molecular weight of 500 or less

• It should have fewer than five hydrogen-bond donating functionalities

• It should have fewer than 10 hydrogen-bond accepting functionalities

• The substance should have a calculated log P (clog P) between approximately -1 and +5

The Lipinski rule of five is thus not a rule comprising five paragraphs but simply an empirical rule, where the number five occurs several times. The rule is a helpful guide rather than a law of nature.

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