Drug design, metabolic aspects

The editors have chosen topics from both important therapeutic areas and from work that advances the discipline of medicinal chemistry. For example, cancer, metabolic syndrome and Alzheimer s disease are fields in which academia and industry are heavily invested to discover new drugs because of their considerable unmet medical need. The editors have therefore prioritized covering new developments in medicinal chemistry in these fields. In addition, important advances in the discipline, such as fragment-based drug design and other aspects of new lead-seeking approaches, are also planned for early volumes in this series. Each volume thus offers a unique opportunity to capture the most up-to-date perspective in an area of medicinal chemistry. 

The carbohydrate metabolism of cestodes has been more extensively studied than any other aspect of metabolism it has been the subject of a number of reviews (39,41,101,102,104,129,221,398,490,492,673,698, 759,816, 911, 931). Much work in this area has been aimed at the identification of biochemical steps which might differ substantially from the host metabolism and which may, therefore, be of value for rational drug design. Unfortunately, in practice, the approach has not proved to be very rewarding and virtually all useful drugs against cestodes have been developed empirically rather than rationally. The chemotherapy of cestodes will not be covered here as this aspect has been comprehensively reviewed (113, 114, 190, 735, 895, 946). 

The word drugability is often used to cover all aspects of a molecule beyond initial potency. A potential drug compound must overcome many challenges in order to be a successful therapeutic. Critical components of drug design include absorption, permeation, distribution, metabolism, stability, specificity (does it do more than... 

The drug PO incorporates aspects of the first three items in the preceding shopping list with some success. Acetate hydrolysis, as the metabolic inactivation route, however, fails to meet the requirements of item 4. The introduced atracurium besylate (Tracrium, Fig. 8-15), however, does meet the requirements. The following discussion then will pertain to the chemical logic that went into the design of atracurium. 

In the earliest research with DET and the related dialkyltryptamines, the chemistry of metabolism was studied for any clues that could explain the activity of these materials. It must be remembered that this was in the heyday of the concept of psychotomimesis, the search for drugs that would imitate the psychotic state. What an appealing concept, that there might be a drug that could produce the syndrome of mental illness and thus be an accepted model for designing some treatment for it. There was a delicious search made at that time (the 1950 s) for names that could be given to these remarkable substances that would obscure any spiritual or positive aspects, so that one could present one s findings into the orthodox medical literature. 

The frequently used acronym LADME, which stands for liberation, absorption, distribution, metabolism, and excretion, broadly describes the various biopharmaceutical processes influencing the pharmacokinetics of a drug. Since each of aspect of LADME can influence the pharmacokinetics of a drug and ultimately the design of controlled release delivery devices, this section will review and explain the relationship between LADME processes and eight common pharmacokinetic parameters (F, K, Vd, tm, Cl, ha, tmax, Cp jnax). 

---