Lipophilic lead molecules

However, the identification of increasingly lipophilic lead molecules, the physicochemical properties of which (low aqueous solubility and high log Ps) suggest a natural predisposition for increased plasma lipoprotein binding, has increased interest in the possible pharmacokinetic, therapeutic, and toxicological ramifications of drug binding to plasma lipoproteins. 

However, when up to 74% phospholipid fractions are used, severe experimental problems arise. With lipophilic sample molecules, the use of concentrated phospholipid artificial membranes leads to two unwanted effects (1) near-complete membrane retention (90-100%) and (2) highly diminished permeability (extinguished in some cases). Both of these effects are presumably due to excessive drug-membrane binding. 

Overall, several useful concepts emerge from these analyses. Different targets and routes of administration may require biased property distributions and screening libraries for successful lead optimization. This could influence the eventual chances of project success and should be taken into account early by project leaders. Once more, optimization focused on potency has been shown again to lead to larger molecules which increases the potential for poor ADME properties. The extent of any ADME issues would of course depend on the structure of lead molecule. Finally, larger, more lipophilic molecules historically have an increased rate of failure in the clinic. 

Most of these steps result in a reduction in lipophilicity compared to the parent molecule. These reductions in lipophilicity lead to increased renal clearance and effectively permit the voiding of the dose from the body as illustrated in Figure 5.6. 

Antioxidants. Excessive concentrations of ROS can have serious effects on membranes, nucleic acid bases and proteins (Section 3.1.3). If uncontrolled, mutations and membrane damage could lead to cell death. To minimize damage, defensive control systems exist. Besides enzymes, there are hydrophilic- and lipophilic-soluble molecules called antioxidants , scavenging free radicals to prevent destruction of cellular biomolecules crucial for cell viability. Non-enzymatic biological antioxidants include tocopherols, carotenoids, qui-nones, bilirubin, steroids, ascorbate, uric acid, GSH, cysteine and metal-binding proteins, such as ferritin (Krinsky, 1992). 

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