Drug Discovery and Development by C. O. Okoro, Ph.D.      

 Chem 4000-Introduction to Medicinal Chemistry


The process varies from one pharmaceutical company to another. However,  there are five stages of the drug development process.


1. Disease pathogenesis and assay development.

Biologist and physicians must unravel the complex pathways that lead to a specific disease.  They will identify the target (enzyme or receptor).  The modulation of the target is expected to cure or manage the disease.

Biochemists will develop assay to determine the effect of small molecules on the target.


2. Finding a lead Compound

Now that the assay have been developed at the first stage, chemists must search for leads for further refinement.  The chemist looks for a single property in the compounds tested and selects only those that show significant activity in the assay.  Natural products as source for lead is highly rewarding.  They offer the best opportunities for drug discovery.  The downside, however, include isolation and structure determination, which is often laborious and expensive. Alternatively, chemists design and synthesize several compounds, often with the help of robotics and combinatorial techniques.


Over the last decades, pharmaceutical companies, as well as specialist suppliers have amassed vast libraries of compounds, which are screened to provide leads for developing new drugs.


3. Optimizing a lead Compound

Once a suitable lead have been identified, a chemist refines itís chemical structure in order to improve both itís activity in the assay and itís physicochemical properties in a process called rational drug design.  The relationship between the structure of a molecule and itís biological activity is explored by designing, synthesizing, and testing a series of analogs.  The resulting structure activity relationship (SAR) are then used to design the next generation of compounds in an iterative process. Computer modeling can be useful at this stage, if structural information about the target is known, such as x-ray crystallography).  X-ray snapshots of ligands bound to their targets are invaluable to the drug designer, because they reveal the interaction between the compound and itís receptor at the molecular level.  Those regions of the molecular structure found to be essential to the binding and biological activity are identified and optimized. Other regions can be fine-tuned to give the most desirable physical and chemical properties, such as bioavailability, solubility, and stability towards chemical and biological degradation and other types of metabolism in vivo.  These features are important to the success of the drug.  Solubility is essential for proper absorption, and distribution. Oral administration demands that the drug be stable to the acidic environment of the stomach.


4. Developing a Drug

After a drug candidate has been found, larger quantities are then needed.  Batches of upto a few kilograms are prepared for further tests, such as toxicity and animal studies in order to determine how the drug will behave in a living system (in vivo).  Many drug candidates fail at this stage due to toxicity or metabolism problem.  A compound that is active in biochemical assays may have no activity in vivo.  If the drug candidate passes these hurdles, production is scaled-up for large and reliable supply. Synthetic chemists may have to re-evaluate the synthetic route.  In a manufacturing process, the overall efficiency (cost and time, and reproducibility of the synthetic route, along with the degree of purity of the final product are crucial to the success of the venture.  Process development chemists also seek to limit the use of toxic or dangerous materials and solvents, to ensure personnel safety and to minimize the environmental impact of the synthesis.  Chemists also play role in drug formulation, which helps the body make the best use of the active component; permits administration to be as simple and convenient as possible; and improves the shelf life of the final product.  With a reliable and plentiful supply provided by pilot plant production the drug candidate can then move into clinical trials.


5. Clinical trials

This does not involve chemists directly.  However, in order to proceed with clinical trial, a company must fulfill two criteria: (1)must produce objective evidence of safety and efficacy (20evidence for itís advantages over existing treatments.  There are three phases of clinical trials.

            Phase I Ė The drug is given to a small group of healthy subjects to determine safe and tolerable dosage levels and investigate drug metabolism


            Phase II Ė This phase involves several hundred patients.  It is used to establish effective doses


            Phase III Ė At this phase the drug candidate must have passed phases I and II.  This phase involves several thousand patients at various sites.  New treatment is compared to existing treatments and sometimes to placebo, usually in double-blind studies in which even the doctor does not know which treatment is being used.  Analysis of data collected lead to FDA approval or disapproval.


            Phase IV Ė This phase is optional for FDA approval.  It involves post-marketing studies undertaken by some companies even in the absence of a regulatory mandate.  It provides information on the effects of the drug over a much larger patient population and longer timescale than is possible during phase II and III trials.  Adverse side effects found during phase IV studies can result in the restriction or withdrawal of a drug.