Basic Principles in Lead Development and Optimization

Potency, efficacy, and selectivity are essential but certainly not the only parameters to fulfill for a pharmacologically active compound to become a therapeutic drug. A large number of additional requirements have to be met, the most important of which have been summarized in the acronym, ADME (Section I.4), which actually should be extended to ADME-Tox (ADME as well as toxicity). Obviously, the drug must reach the site of action in a timely manner and in sufficient concentration to produce the desired therapeutic effect.

After oral administration, the drug must survive the acidic environment of the stomach. In the small intestine, the bulk of absorption takes place. Here, the pH is neutral to slightly acidic. In the gastrointestinal system metabolism can take place. The presence of digestive enzymes creates particular problems for polypeptide drugs, and the gut wall is fairly rich in oxidative enzymes.

Unless the drug acts as a substrate for active energy-requiring uptake mechanisms, which normally facilitate uptake of, for example, amino acids and glucose, it must be significantly unionized to penetrate into the body. Following absorption, the blood rapidly presents the drug to the liver, where Class I metabolic transformations (oxidation, hydrolysis, reduction, etc.) and in some cases Phase II transformations (glucuronidation, sulfatation, etc.) take place. The polar reaction products from these reactions are then typically excreted in the urine or feces.

The rate of absorption of drugs, their degree of metabolic transformation, their distribution in the body, and their rate of excretion are collectively named pharmacokinetics. This is in effect the influence of the body on a drug as a function of time. The interaction of the drug with its receptors, in the broad sense of the word, and the consequences of this interaction as a function of time are pharmacodynamics.

Both of these characteristics are alone governed by the drug's chemical structure. Thus, the medicinal chemist is expected to remedy any shortcomings by structural modifications. In addition to ADME-Tox, a number of other characteristics must also be satisfactory, such as:

• Freedom from mutagenesis

• Freedom from teratogenecity

• Chemical stability

• Synthetic or biological accessibility

• Acceptable cost

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