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III. Chemical Synthetic Discovery |
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Over the last 75 years, the majority of new molecules have come from synthetic chemistry. In cardiology, beta blockers and calcium channel blockers have revolutionized cardiovascular therapeutics. Beta agonists in respiratory therapy and H2 antagonists in gastrointestinal ulcer disease therapy are two other examples of the work of synthetic chemists that has greatly changed our treatment of patients. These advances represent creations of synthetic chemistry, but also the well-proven model of finding a useful transmitter in a physiologic system, finding a receptor on which the transmitter acts, and then modifying the agonist's structure to find a specific antagonist. This has worked well with major advances in a number of fields. As new receptors and new physiologic systems are revealed, the synthetic chemist will surely continue to make considerable contributions to the field of drug discovery. For instance, as the role of the endothelium is understood better, its impact on pharmaceutical research has greatly expanded. What was once called EDRF (Endotheliol Derived Relaxing Factory) has been characterized as a locally released gas, nitric oxide. Studies on endothelial function have found endogenous substances involved in the modulation of vasodilation and vasoconstriction at the local endothelial level. There are endogenous substances opposing the vasodilating properties of nitric oxide. Endothelin is one of these transmitters and the development of specific endothelin antagonists is an exciting new field. Whether these endothelin antagonists will be effective therapies in angina, hypertension, or congestive heart failure remains to be determined, but the process shows that the synthetic discovery of drugs, combined with physiologic transmitter research, is still spawning drugs of great potential. Even here, with well-established approaches, we see the influence of the information age. Employing computers to determine receptor structure and thus possible receptive blockers has become a useful tool in the drug discovery process. Computer-assisted drug synthesis has great potential. In fact, there is at least one company that has this technology central to its commercial activities. The revolution in this aspect of synthetic chemistry is analogous to the computer revolution in the animation industry. Where dozens of artists once toiled, there are now computers creating life-like animations that were not feasible previously. The same revolution that the company Silicone Graphics created for animation will be occurring for the chemical synthetic industry. Besides design, the categorization of synthetic pathways can readily be computerized. The application of computer sciences to chemistry will also lead to considerable advances in this field. The application of computers to the steps beyond modeling systems, such as identifying chemical structures and automatically developing synthetic approaches, will be of considerable impact. Synthetic antagonists with optimum potency can be developed from a host of chemical possibilities. |
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