Adme And Medicinal Chemists

Although ADME assays are usually performed by analytical chemists, medicinal chemists—the molecule makers—need to have some understanding of the physico-chemical processes in which the molecules participate. Peter Taylor [17] states:

It is now almost a century since Overton and Meyer first demonstrated the existence of a relationship between the biological activity of a series of compounds and some simple physical property common to its members. In the intervening years the germ of their discovery has grown into an understanding whose ramifications extend into medicinal chemistry, agrochemical and pesticide research, environmental pollution and even, by a curious re-invention of familiar territory, some areas basic to the science of chemistry itself. Yet its further exploitation was long delayed. It was 40 years later that Ferguson at ICI applied similar principles to a rationalization of the comparative activity of gaseous anaesthetics, and 20 more were to pass before the next crucial step was formulated in the mind of Hansch. ... Without any doubt, one major factor [for delay] was compartmentalism. The various branches of science were much more separate then than now. It has become almost trite to claim that the major advances in science take place along the borders between its disciplines, but in truth this happened in the case of what we now call Hansch analysis, combining as it did aspects of pharmacy, pharmacology, statistics and physical organic chemistry. Yet there was another feature that is not so often remarked, and one with a much more direct contemporary implication. The physical and physical organic chemistry of equilibrium processes— solubility, partitioning, hydrogen bonding, etc.—is not a glamorous subject. It seems too simple. Even though the specialist may detect an enormous information content in an assemblage of such numbers, to synthetic chemists used to thinking in three-dimensional terms they appear structureless, with no immediate meaning that they can visually grasp. Fifty years ago it was the siren call of Ehrlich's lock-and-key theory that deflected medicinal chemists from a physical understanding that might otherwise have been attained much earlier. Today it is glamour of the television screen. No matter that what is on display may sometimes possess all the profundity of a five-finger exercise. It is visual and therefore more comfortable and easier to assimilate. Similarly, MO theory in its resurgent phase combines the exotic appeal of a mystery religion with a new-found instinct for three-dimensional colour projection which really can give the ingenue the impression that he understands what it is all about. There are great advances and great opportunities in all this, but nevertheless a concomitant danger that medicinal chemists may forget or pay insufficient attention to hurdles the drug molecule will face if it is actually to perform the clever docking routine they have just tried out: hurdles of solubilization, penetration, distribution, metabolism and finally of its non-specific interactions in the vicinity of the active site, all of them the result of physical principles on which computer graphics has nothing to say. Such a tendency has been sharply exacerbated by the recent trend, for reasons of cost as much as of humanity, to throw the emphasis upon in vitro testing. All too often, chemists are disconcerted to discover that the activity they are so pleased with in vitro entirely fails to translate to the in vivo situation. Very often, a simple appreciation of basic physical principles would have spared them this disappointment; better, could have suggested in advance how they might avoid it. We are still not so far down the path of this enlightenment as we ought to be. What is more, there seems a risk that some of it may fade if the balance between a burgeoning receptor science and these more down-to-earth physical principles is not properly kept.

Taylor [17] described physicochemical profiling in a comprehensive and compelling way, but enough has happened since 1990 to warrant a thorough reexamination. Then, combichem, high-throughput screening (HTS), Caco-2, IAM, CE were in a preingenuic state; studies of drug-partitioning into liposomes were arcane; instrument companies took no visible interest in making pKa, log P, or solubility analyzers; there was no biopharmaceutics classification system (BCS); it did not occur to anyone to do PAMPA. With all that is new, it is a good time to take stock of what we can learn from the work since 1990. In this book, measurement of solubility, permeability, lipophilicity, and charge state of drug molecules will be critically reexamined (with considerable coverage given to permeability, the property least explored). Fick's law of diffusion [18] in predicting drug absorption will be reexplored.

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