Safety aspects have become an outstanding issue in the process of drug discovery and development. Until 15 years ago drug discovery and evaluation was a sequential process starting with the selection of the most active compound from a series of newly synthesized compounds by means of special pharmacological assays. Safety aspects were addressed by pharmacological testing of the selected compound in high doses in tests directed at indications other than the intended indication of the new compound. These tests were followed by pharmacokinetic studies which were mainly aimed at confirming of a suitable half-life time and at oral activity. Safety aspects relied mostly on toxicity studies which however gave information on changes of organ structure rather than on organ function. Toxicological and pharmacokinetic studies were adapted to the progress of studies in clinical pharmacology and clinical trails. This sequential strategy has been abandoned for several reasons:
Some negative effects on organ function e.G. Ventricular tachy-arrhythmia were detected too late. On the other hand negative findings in chronic toxicity studies in animals turned out to be irrelevant for human beings.
New scientific approaches e.G. Combinatorial chemistry high-throughput screening in silico models pharmaco-genomics and pharmaco-proteomics offered new possibilities.
There are several examples which show that the druggability of compounds was considerably underestimated when the probability of ...
