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ADME/PK Considerations in Combinatorial Library Design

It is only very recently that the need to design libraries of ''drug-like'' molecules has become a central topic among the practitioners of combinatorial or parallel synthesis in the life science arena [3, 4]. A number of ''rules'' have been established from the analysis of various databases in order to aid chemists in library design with respect to ''drug-likeness'' [5-9], some of which were discussed in Chapter 25. In some companies, rules of that kind have been implemented in software tools that are used as guides in library design. But what exactly does ''drug-likeness'' mean?

Most potential drugs are intended for oral application. In order for a compound to reach its site of action, it has to cross several barriers within the body. After intake, it has to be sufficiently water soluble in the lumen of the gastrointestinal (GI) tract for it to be absorbed. It also has to be sufficiently stable in this environment, which has, for instance, marked differences in pH values. On the other hand, the compound should not be too hydrophilic or too bulky because then it might remain in the gut lumen and eventually be excreted rather than being absorbed. Hence, some degree of lipophilicity is required for a compound to be absorbed through the lipid membrane of the gut wall, but compounds with a molecular volume greater than a certain threshold range are restricted from being (passively) absorbed. However, if the compound is too lipophilic, it might remain in the membrane or stick to other biological material in the gut and might not reach the portal vein. In the following sections, the factors which govern absorption, for example permeability and solubility, will be discussed in greater depth. After being absorbed, a compound has to pass through the liver, where it might be metabolized, it might be transformed into active, inactive or even toxic metabolites, or it might be excreted via the bile. Having passed through the liver, the compound is part of systemic circulation. As such, it has to be stable against plasma components, e.g. certain enzymes. It has to be distributed within the body and must penetrate the respective target tissue. For that purpose, it is likely that the compound again has to cross one or even several lipid membranes. Simultaneously, the compound is subject to continued hepatic and renal clearance.

From this brief description, it is obvious that a drug is more than just a pharmacophore. It must possess properties that allow a sufficient proportion of the ad ministered amount of drug molecules to reach their site of action in order to trigger the desired pharmacological effect. In recent literature, these properties are referred to as ''ADME/PK'' properties, where ADME stands for absorption, distribution, metabolism, and excretion and PK stands for pharmacokinetics.

Once the importance of ADME/PK properties has been recognized, it is desirable to incorporate ADME/PK considerations early into the hit- or lead-finding process because the likelihood of successful optimization is higher and the time it would take to find a suitable drug candidate is shortened when the starting point already possesses some quality features [10]. Especially in library design, it would be advantageous to filter virtual libraries in order to select a sublibrary containing discrete members with some minimum likelihood of being orally bioavailable and to synthesize and screen just the subset [3]. For that purpose, tools are needed which allow an estimation of the ADME/PK properties from the chemical structure [11]. The physicochemical properties of a compound that underlie ADME/PK behavior and how these can be predicted are discussed below. A review that summarizes the current status of the entire field of ADME/PK optimization was published recently [12].

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