Developing New Drugs
Pp. 128-162 (35)
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 . 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.
New chemical entity, NCE, investigational new drug, IND,
quantitative structure-activity relationships, QSAR, agonist, antagonist, cGMP,
Park University Chemistry Department 8700 NW River Park Drive Parkville, MO 64152 USA.