ADME studies screening

Table 2.2 contains a list of ADME-PK assays that are routinely used to provide information via in vitro assays, lead optimization screens, and in vivo PK studies [22], Each assay is developed and applied with the intent of providing a quick survey of ADME-PK properties. Certainly, the workflow of drug discovery activities can often be depicted in a linear, stepwise fashion according to the ADME-PK screens highlighted in Table 2.2. However, such a workflow would not take into consideration the dynamics of a drug discovery program nor would such a workflow depict the differences that exist between different programs (i.e., diabetes, cancer, cardiovascular). The fact is that the discovery process is often initially supported with a standard set of ADME-PK assays that can be viewed as somewhat compulsory and highly iterative.

From an analysis of the key properties of compounds in the World Dmg Index the now well accepted Rule-of-5 has been derived [25, 26]. It was concluded that compounds are most Hkely to have poor absorption when MW>500, calculated octanol-water partition coefficient Clog P>5, number of H-bond donors >5 and number of H-bond acceptors >10. Computation of these properties is now available as a simple but efficient ADME screen in commercial software. The Rule-of-5 should be seen as a qualitative absorption/permeabiHty predictor [43], rather than a quantitative predictor [140]. The Rule-of-5 is not predictive for bioavail-abihty as sometimes mistakenly is assumed. An important factor for bioavailabihty in addition to absorption is liver first-pass effect (metaboHsm). The property distribution in drug-related chemical databases has been studied as another approach to understand drug-likeness [141, 142]. 

Benzodiazepinones such as 4 [14] have been claimed as PDE2 inhibitors, as have oxindoles related to 5 [15]. Compound 5 was reported to have an IC50 of 40 nM against PDE2. Preliminary ADME screening showed 5 to have the physicochemical and pharmacokinetic characteristics that should allow use as a tool to study PDE2 function in more detail [16]. 

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