- Design or identification of a lead (prototype) compound (section 3.2)
- Synthesis and initial biological evaluation of the lead compound (section 3.3)
- Optimization of the lead compound for the pharmacodynamic phase (section 3.4)
- Optimization of the lead compound for the pharmacokinetic and pharmaceutical
phases (section 3.5) - Pre-clinical and clinical evaluation of the optimized lead compound analog (section 3.6)
The remainder of this chapter will discuss these five steps in drug optimization within
the context of the multiphore method of drug design.
3.2 IDENTIFICATION OF A LEAD COMPOUND
Lead compounds are still a sine qua non of drug design. A lead compound (pronounced
“le-d” and not to be mistaken for a salt of element 82) is invariably an organic molecule
that acts as a prototype drug around which future optimization is centered and focused.
Identifying a lead compound is the key to starting the drug discovery engine. There are
several well-tested methods for uncovering or identifying lead compounds as prototype
agents around which to design and optimize a drug molecule:
- Serendipity
- Endogenous sources (drug candidates from molecules within us; e.g., insulin for
diabetes) - Exogenous sources: ethnobotany (drug candidates from natural product sources)
- Rational drug design
- High throughput screening programs
- Genomics/Proteomics
Elegant though some of these may sound, serendipity has historically been the most
successful discoverer of drugs.
3.2.1 Lead Compound Identification—A Short
History of Drug Discovery“How have drugs historically been discovered? Can these traditional techniques be fur-
ther exploited to help discover new and better drugs?” The answer to the latter question
is probably “no”!
Since the dawn of humankind, efforts have been made to discover remedies for the
ailments of life. Although there are numerous examples of the trials and tribulations
associated with these efforts, the story of epilepsy affords many instructive anecdotes.
The failure of premodern physicians to develop adequate therapies reflected their
inability to gain a viable mechanistic understanding of epilepsy. In primitive times, sur-
gical “therapies” for epilepsy included trephiningholes through the patient’s skull in
order to release “evil humours and devil spirits.” The ancients also employed a varied
and bizarre assortment of ad hoc “medical” therapies, ranging from rubbing the body
of an epileptic with the genitals of a seal, to inducing episodes of sneezing at sunset. In
early Roman times human blood was widely regarded as curative, and people with
epilepsy frequently sucked the blood of fallen gladiators in a desperate attempt to find
a cure. Charlatans would also offer (for a generous fee, of course) to massage the heads
108 MEDICINAL CHEMISTRY