Potency-based screening

The hits from potency-based screens should be evaluated, as early as possible, with a set of profiling (or selectivity) assays and toxicology testing from early... 

Figure 6.2. Strategies for the design of decision trees for new compound evaluation. ADME-based screens can be incorporated in many places in a decision tree, three examples are illustrated A, ADME screens are run as a panel in parallel with early activity screens, compounds proceed to further biological screens after meeting set criteria B, ADME screens are run after a compound meets set potency criteria and compounds proceed to further biological screens after meeting set ADME criteria C, critical ADME screen (metabolic stability in this case) is run on compounds that meet potency criteria and then full ADME screen panel is run before compounds proceed.

Most drug metabolism-based screens are performed during the lead optimization phase of drug discovery. Lead optimization begins once a compound is identified from primary screens and the desired potency, selectivity, and mechanism of... 

These characteristics aim to guide the development of robust, reproducible, and easily implementable probe compounds. Sufficient potency supports necessary target selectivity, and selectivity enables confident associations to be made between target modulation and phenotypic output for hypothesis testing. Membrane permeability, while often implied by the presence of a phenotypic response in a cellular or organism-based screen, also envelops passive and active transport as well as potential active reverse cellular efflux. 

The first non-peptide oxytocin antagonists, based on a spiropiperidine template, were described by Merck in 1992 [68-70]. The binding affinity data for key compounds from this series are summarised in Table 7.2. The initial screening hit, L-342,643, (23), had modest (4/iM) affinity for rat uterine oxytocin receptors and very little vasopressin selectivity [71]. A structure activity relationship (SAR) study was carried out around this template, focussing on the toluenesulphonamide group. This work led to the identification of bulky lipophilic substitution as key to improved oxytocin potency, while the introduction of a carboxylic acid group led to improved... 

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