about the binding process; they do not tell if the drug is an agonist or antagonist. Functional
in vitroassays with a measurable biological outcome are required to tell whether a
compound is functioning as an agonist or an antagonist.
By far the most useful assay is the in vivoassay. Regrettably but understandably, this
assay is the most labor-intensive and costly. In vivoassays give the highest quality
information about the efficacy of a lead compound. In vivomodels are accurate animal
models of a human disease. Ideally, a candidate drug molecule should not be advanced
in the development process unless it demonstrates good to excellent efficacy in an
appropriatein vivomodel.
3.3.4 Deciding to Optimize a Lead Compound
Once a biologically active lead compound has been identified (i.e., designed, synthe-
sized, evaluated), the next decision is whether to proceed with the optimization of the
lead compound. If the disease is important and if the lead compound has promising
132 MEDICINAL CHEMISTRY
Figure 3.5 The synthesis of diazepam is initiated by the double acylation of an aromatic amine
with an aromatic acid chloride. A second equivalent of the p-chloroaniline leads to a six-membered
ring with two nitrogens. This is hydrolytically opened to expose a free amino group which reacts
with an aminoester to yield a seven-member ring. The amide nitrogen is then methylated.