Chapter 3

Developing New Drugs

Robert E. Smith


Drugs are sometimes developed in distinct phases. Usually, the drug discovery and development process can be divided into these stages: select a disease, identify a target, find a lead compound, quantify drug-target interactions, determine solubility, pharmacokinetics and toxicity, improve the lead compound, find the best way to deliver the drug to the patient, manufacture the drug, apply to the FDA to do investigational studies, do the clinical studies, apply to the FDA for drug approval, and do post-registration studies [1]. The solubility, pharmacokinetics and toxicity are determined in GLP studies. Similar compounds are tested in the lab and by computer modeling, so structure-activity relationships (SARs) can be developed. Eventually, a new chemical entity (NCE) or investigational new drug (IND) is selected for further evaluation. The optimum method for drug delivery is selected. A manufacturing process is developed and documented according to cGMP. Potential targets include membrane bound receptors (such as GPCRs, tyrosine kinases and intracellular nuclear receptors). Agonists bind to receptors and mimic the action of the endogenous ligand. Antagonists bind to receptors and block the binding and subsequent action of the endogenous ligand. Enzymes, DNA, protein transporters, ion channels and pumps are other potential targets.They are part of the cellular network. Most nodes in cellular networks can be thought of as problem solvers. For example, the enzymes in glycolysis catalyze reactions that are needed to produce energy. Hubs, though, act as problem distributors. They distribute signals to many other nodes, in response to changes in the intra- and extracellular environments. Both problem solvers and distributors can be predictable. Another type of node is less predictable and is called a creative element. These nodes are quite dynamic and monitor almost the entire network by continuously changing the structures of the proteins to which they are linked. Creative elements may have few links at a given time, but can increase their connectivities when needed.

Total Pages: 128-162 (35)

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