By Bernard Testa, Stefanie D. Krämer, Heidi Wunderli-Allenspach, Gerd Folkers
Informatics and robotics are the workhorses of a technological revolution in drug learn. On them are established combinatorial chemistry, which yields compounds by way of the numerous millions, and high-throughput bioassays, which monitor them for task. the implications are avalanches of 'hits', which invade the databases like swarms of locusts. yet faraway from being an endemic, those innumerable compounds turn into a blessing if adequately screened for 'drugability', i.e., for 'drug-like' houses equivalent to sturdy pharmacokinetic (PK) habit. Pharmacokinetic profiling of bioactive compounds has, therefore, turn into a sine qua non for cherry-picking the main promising hits. simply as very important, yet much less seen, are the structure-property and structure-ADME relatives, which emerge from PK profiling and supply invaluable suggestions whilst designing new man made sequence. hence, the screening, layout, and optimization of pharmacokinetic houses has develop into the bottleneck and an immense problem in drug examine. To shorten the time-consuming improvement and excessive fee of attrition of lively compounds finally doomed through hidden pharmacokinetic defects, robust organic, physicochemical, and computational ways are being built, whose ambitions are to extend the scientific relevance of drug layout and to dispose of once attainable compounds with adverse physicochemical homes and pharmacokinetic profiles.
The profiling of ADME homes (absorption, distribution, metabolism, and excretion) is the subject of this booklet. Following the extreme good fortune of the former paintings ('Pharmacokinetic Optimization in Drug learn: organic, Physicochemical, and Computational Strategies', Eds. B. Testa, H. van de Waterbeemd, G. Volkers, R. man, Verlag Helvetica Chimica Acta, Z? 2001, 655 pages), there has been a necessity for an basically new version targeting the most recent theoretical and technological breakthroughs. during this distinctive paintings, foreign gurus and practising specialists from academia and supply state of the art shows of techniques, equipment and applied sciences now in use or improvement in drug learn. The organic options emphasised within the e-book comprise phone cultures, drug-metabolizing enzymes, transporters and plasma protein binding. The physicochemical thoughts concentrate on synthetic membrane-permeability assays, on solubility and lipophilicity and comparable molecular houses as components and predictors of pharmacokinetic habit, and on balance and solid-state houses. Computational ideas comprize the exploration of estate areas, pharmacophore looking to foretell biotransformation and enzyme inhibition, and professional platforms to technique biopharmaceutical profiling info.
as well as its 28 chapters, the publication contains a CD-ROM containing the invited lectures, oral communications, and posters (in complete model) provided on the 3rd LogP Symposium, 'Physicochemical and organic Profiling in Drug Research', held on the Federal Institute of expertise (ETH) of Z?in March 2004.