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With a heightened receptor selectivity and potency, the increased yield of these procedures will be noticeable. |
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However, the information age applications to synthetic modeling will be inherently limited unless we can improve our screening techniques. For many years, I have given considerable thought to the link between drug synthesis, discovery, and development. Almost 15 years ago, I had the good fortune to visit Janssen Pharmaceuticals and discuss the drug discovery process with Paul Janssen, a genius in the field. I was most impressed with his grasp of chemistry, his diverse interests, and his unparalleled success in the discovery of novel entities. Janssen was a chemist looking for novel compounds that could then be assessed to find biologic activity. A promising new compound would be processed through hundreds of models, looking for possible pharmacologic activity. The question arose about the ability to screen for biologic activity, a critical linkage point in the discovery and development process, and one to which the efficiencies and great possibilities of the information age can be effectively applied. |
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The Janssen approach fascinated me, but to this day has created deep abiding concerns. Since I have been interested in the field of antiarrhythmic drug development for many years and have participated in all stages of drug development from chemical synthesis to the clinical arena of programmed electrical stimulation studies, I was particularly interested in Janssen's approach as applied to antiarrhythmic pharmacology. I had been working on Lorcainide, a drug Janssen developed at Bersa, and wondered how this compound came out of discovery and how it compared to other agents screened. Janssen employed a costly dog model of PVC suppression post-coronary artery ligation. Lorcainide, being a Ic Vaughan Williams' agent, was most effective in this model as a sodium channel blocker with slow on and off kinetics to the sodium channel would be predicted to act in this type of model. But PVC suppression and the Ic agents have not shown prolongation of life in post-MI studies. The type-III agents appear to be most effective clinically, although not definitively shown to prolong life in randomized controlled trials. However, a meta-analysis of drugs of the type-III variety and, specifically, amiodarone, have suggested them to be far more effective with much less proarrhythmia than the sodium channel blockers. One might wonder what would be the effect of the clinically valuable agent amiodarone in the screening model that Janssen was using to pick out his antiarrhythmic to go into development. In fact, the records at Bersa were so accurate that the scientists in that department could look up the results in a few minutes and describe the actions of other known antiarrhythmic agents in the drug model. The answer they gave me was that amiodarone was much less effective and, in fact, hardly effective at all in the model in which Lorcainide was so very effective. It is no wonder that the pharmaceutical industry in the 80s found a host of Ic agents (flecainide, encainaide, lorcainide, |
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