Lipophilic hits

A specific example of prudent hit-to-lead design is illustrated in the development of soluble epoxide hydrolase inhibitors by Tanaka et al. [16]. By placing more emphasis on ligand efficiency of hits rather than the better absolute potency of larger and more lipophilic hits, they explored the SAR of the cyclopropyl amide shown in Figure 17.5. While the hit compound has only 0.5 micromolar activity, it has quite good ligand efficiency and is amenable to rapid... 

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... 

The trend toward decreased stability of compounds with increased lipophilicity and MW is obvious. This analysis can provide information about the roles of these two properties in contributing to clearance for this series. Again, the important question for hit triage decision making is how the hypothesized structure-clearance trends correlate to the property trends for other relevant biological properties. 

The use of high-throughput screening (HTS) results in hits and leads that are more lipophilic than optimized drugs [24]... 

When a validated hit is selected as a promising lead compound, its physicochemical profile must be studied in detail. Sophisticated in silica approaches such as 3D lipophilicity predictions coupled with extensive conformational analysis [49, 50,135,146] and molecular field interactions (MIFs) [147-150] could be helpful to better interpret the detailed experimental investigations of their ionization constants by capillary electrophoresis or potentiometric titrations [151, 152] and their lipophilicity profiles by potentiometry [153]. However, these complex approaches cannot be performed easily on large number of compounds and are generally applied only on the most promising compounds. 

The question hits the big unknown in explaining the cation permselectivity of the neutral carrier systems mentioned in my report. In the solvent polymeric membranes we studied, the contribution of anions to the electrical current (anion transport number) is usually negligible if hydrophilic anions (e.g., Cl ) are involved. In the presence of lipophilic anions (e.g., SCN ) there exists some contribution of anions to the total ion flux across the membrane [see Anal. Chem., 48, 1031 (1976)]. The reasons for such a behavior may be ... 

A recently reported tool for hit evaluation and prioritization is ligand lipophilicity efficiency (LLE).21 LLE is calculated as the difference between the negative logarithm of a hit s binding affinity, such as —log /C50 or —log KD, and the logarithm of a hit s partition coefficient, such as log P or clog P (Equation 10.2). 

The following diagrams show four hits from an assay with their activities (ED50) and lipophilicities (clog P). Which of the four hits is the most attractive based on its ligand lipo-philicity efficiency ... 

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