Drug compound properties

Frostell-Karlsson, A., Widegren, H., Green, C. E., Hamalainen, M. D., Westerlund, L., Karlsson, R., Fenner, K., Van De Waterbeemd, H. Biosensor analysis of the interaction between drug compounds and liposomes of different properties a two-dimensional characterization tool for estimation of membrane absorption. /. Pharm. Sci. 2005, 94, 25-37. 

At the hit triage stage, it is most common to be able to characterize sets of compounds in a kinetic solubility assay. In the assessment and utilization of these data, the potential disconnects between kinetic and thermodynamic solubility must be considered. Low kinetic solubility for a series of compounds should lead a project team to be concerned about the behavior of compounds in biological assays and buffers, as well as the potential for optimizing drug-like properties in that series. Conversely, while high kinetic solubility is a desirable property, chemists should still remain cognizant of the need to assess thermodynamic solubility as compounds are further optimized. 

The main reasons for the popularity of the Caco-2 cell line are that the cells are easy to maintain in culture, and they develop unusually high degree of differentiation spontaneously under standard culture conditions. In fact, Caco-2 is the only human intestinal cell line that has been found so far spontaneously to undergo functional enterocytic differentiation. The cells exhibit a good reproducibility, robustness and functional properties of human intestinal epithelial cells. The model has proved capable of predicting the oral absorption of a variety of drug compounds [see references in 10]. 

The incorporation of fluorine into a molecule has been widely used to alter the pharmacokinetic properties and overall drug-like properties of compounds. This includes affecting the metabolism, oral absorption, and brain penetration of these molecules [18]. Metabolism can be affected by addition of fluorine directly at or adjacent to the site of metabolism. In addition, substitution with fluorine can increase the lipophilicity of compounds which has been shown to dramatically affect both oral absorption and brain penetration. Finally, the electron-withdrawing characteristic of fluorine has been exploited to lower the P-gp liability of compounds and modulate the pKa of adjacent groups which resulted in increased brain exposure. In the following section, representative examples will highlight the powerful nature of fluorine to modulate overall drug-like properties. 

There are a variety of structural classes of compounds that are active against each phosphodiesterase, and evidence suggests that selective inhibitors of PDEs can be identified. The structural diversity of PDE inhibitors provides a multitude of opportunities for development of compounds with drug-like properties. Furthermore, phosphodiesterase inhibition, which avoids direct interaction of a compound with a cell surface or nuclear receptor, may circumvent some of the target selectivity issues that can complicate receptor-based therapeutic approaches. As noted above, the specific subcellular distribution of phosphodiesterase enzymes is a key feature of their ability to modulate intracellular signaling pathways. This localization of the enzyme may minimize non-specific target... 

Apart from the flow rate, of course, properties of the dissolution medium as well as the drug compound influence the... 

The first step in the development of a new dissolution test is to evaluate the relevant physical and chemical data for the drug substance. Knowledge of the drug compound s physical-chemical properties will facilitate the selection of dissolution medium and determination of medium volume. 

Aqueous solubility is probably the single most important biopharmaceutical property that pharmaceutical scientists are concerned with. It has been the subject of computational prediction for several years.20 23 The overall accuracy of the predicted values can be expected to be in the vicinity of 0.5 to 1.0 log units (a factor of 3 to 10) at best. Although a decision on acceptance or rejection of a particular compound cannot be made only on the basis of predicted parameters, these predictions may be helpful to direct chemical libraries with improved drug-like properties.24... 

Further tests are carried out to evaluate the potency and specificity of the isolated lead compounds. This is usually followed by modifications of the compounds to improve properties through synthesis of variations to the compounds via chemical processes in the laboratory and frequently with modifications to the functional groups. The optimized lead compounds go through many iterative processes to keep improving and optimizing the drug interaction properties to achieve improved potency and efficacy. 

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