ADME absorption, distribution lead compounds

As described previously, virtual screening and in silico design will accelerate the discovery of active lead compounds with new chemical scaffolds. The in silico prediction of physicochemical and ADME (absorption distribution metabolism elimination) properties, however, also are very critical for lead development. Actually, pharmacokinetics and toxicity have been identified as important causes of costly late-stage failures in drug development. The recently developed in silico approaches will increase model productivity in fine-tuned lead optimization to improve compound design and lead optimization. 

Leads are compounds that have desired in vitro properties on ADME (absorption, distribution, metabolism, and excretion), are safe and patentable, and their activity is confirmed in first in vivo models. 

An important part of the optimization process of potential leads to candidates suitable for clinical trials is the detailed study of the absorption, distribution, metabolism and excretion (ADME) characteristics of the most promising compounds. Experience has learned that physico-chemical properties play a key role in drug metabolism and pharmacokinetics (DMPK) [1-3]. As an example, physicochemical properties relevant to oral absorption are described in Fig. 1.1. It is important to note that these properties are not independent, but closely related to each other. 

From a DMPK perspective, a common goal is to be able to compare multiple compounds based on their absorption, distribution, metabolism and excretion (ADME) properties as well their preclinical PK properties [8, 12-22]. Therefore, lead optimization typically is performed as an iterative process that uses the DMPK data to select structural modifications that are then tested to see whether the DMPK properties of the series have been improved. This iterative process is shown schematically in Fig. 13.2. Clearly an important element for the successful lead optimization of a series of NCEs is the ability to perform the DMPK assays in a higher throughput manner. The focus of this chapter will be to discuss ways that mass spectrometry (MS), particularly HPLC-MS/MS can be used to support the early PK studies for NCEs in a higher throughput manner. 

The plasma level of a toxic compound is a particularly important parameter, as (i) it reflects and is affected by the absorption, distribution, metabolism, and excretion (ADME) of the compound (fi) it often reflects the concentration of compound at the target site more closely than the dose it should be noted that this may not always be the case such as when sequestration in a particular tissue occurs which may or may not be the target tissue, for example, chlorphentermine (see Fig. 3.19), lead and, polybrominated biphenyls (Fig. 3.20) ... 

With the success of combinatorial chemistry and HTS. more and more new structural entities are created or acquired and lead compounds discovered. As a consequence, there is an increased demand for high throughput measurement of the quality, physiochemical, and pharmaceutical properties of absorption, distribution, metabolism, and excretion (ADME) of these compounds. This increased demand has created opportunities for the application of mass spectrometry to these research activities. 

---