The development and implementation of a novel bioisosteric software program for the development of n

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The drug discovery and approval process are extremely costly and time consuming. The expenses associated with FDA approval are approaching 1.5 billion dollars, which has impacted the way in which pharmaceutical companies approach problems. New lead molecular entities are run through a gauntlet of in vitro, in vivo, and in silico tests to determine their suitability for human use prior to undertaking any clinical trials. Currently most of the drug failures are related to poor pharmacokinetic or toxicity problems, which have been discovered in the late stages of clinical trials. It would be much more preferable from an economic standpoint if drug candidates doomed to fail ultimately in clinical trials can be identified in the earlier stages of drug discovery. Rarely does a drug come to market without extensive modifications having been made to the original lead molecular structure. More often than not, the drug has undergone a series of systematic modifications designed to improve any known pharmacologic and/or toxic deficiencies that have been detected in laboratory and animal model studies. Sometimes these modifications are minor, and other times, there may be so many changes that a completely new compound has emerged that seemingly has little or no similarity to the original lead.

For those lead compounds that do show promise, experimentalists will often make small changes to improve the necessary list of characteristics that are necessary for improved efficacy and pharmacokinetic patterns. These small incremental changes and subsequent biological testing are the basis for structure-activity relationships, which provide drug discovery scientists with information about what molecular features enhance or decrease biological activity. Most commonly, medicinal chemists focus on systematically modifying one part of a potential drug candidate, while leaving the rest of the structure unmodified. Such approaches have yielded commercially successful drug therapies. Perhaps the most highly acclaimed example of such systematic modifications based on physical organic chemistry is cimetidine, which is used for the treatment of stomach ulcers and related gastrointestinal disorders. Cimetidine was the first billion dollar selling medicine. It is not unusual for pharmaceutical laboratories to replace hundreds of substituents in an attempt to find the most effective structure. The basis for many of these changes include historical precedent, ease of synthesis, information gleaned from structural studies, and physicochemical reasons. To find the right substituent, researchers have often invoked the idea of bioisosteres.