A risk assessment of human ether-a-go-go-related gene potassium channel inhibition by using lipophilicity and basicity for drug discovery.

The blockade of human ether-a-go-go-related gene (hERG) potassium channels is widely regarded as the predominant cause of drug-induced QT prolongation. The correlation analysis between the inhibition of the hERG channel (hERG inhibition) and physicochemical properties was investigated by use of in-house quinolone antibiotics as model compounds. In order to establish a simple prediction model of hERG inhibition, we focused on the comprehensible physicochemical parameters such as lipophilicity (log P) and basicity (pK(a)). At first, the risk associated with increasing log P and pK(a) was examined by statistical analysis. It was demonstrated that the risk associated with increasing log P and pK(a) by one unit, respectively, almost identically increased. Consequently, equal attention should be paid to both parameters on hERG inhibition. Next, a prediction model of hERG inhibition which was represented by log P and pK(a) was investigated. As a result, we built the stepwise discriminant prediction model which took advantage of the risk judgment by zone classification. In conclusion, the impact of log P and pK(a) on hERG inhibition was clarified relatively and quantitatively. The quantitative risk assessment established based on both parameters, was considered to be a practical and useful tool in avoiding hERG inhibition and in the rational drug design for drug discovery, especially in lead optimization. Moreover, we also carried out a trend analysis using a different derivative and demonstrated that both parameters were equally significant for hERG inhibition.

Profiling and trend analysis of food effects on oral drug absorption considering micelle interaction and solubilization by bile micelles.

Correlation analysis between food effects on oral drug absorption (food effect) and physicochemical properties is important for efficient drug discovery and contributes to drug design. This study focused on micelle binding and solubilization considering bile micelles in the intestinal fluid. Profiling using about 40 launched drugs demonstrated that those in a high solubilization area (area 1) tended to have a positive food effect, and that drugs exhibiting negative/no food effect tended to coexist in a no/low solubilization area (area 2). In area 1, the solubilization effect by bile micelles was demonstrated quantitatively as an important factor that indicates a positive food effect. In area 2, the relative and quantitative relationships among the membrane permeation rate, dissolution rate, micelle binding and food effect could be clarified by simulation. The improvement of membrane permeability and the suppression of micelle binding are considered to be required to avoid a negative food effect. In conclusion, important factors contributing to the food effect were clarified relatively and quantitatively. Data generated from this profiling may be beneficial to find a solution for negative food effects. Furthermore, this risk assessment of food effects is considered to be a useful tool in rational drug design for drug discovery.

Evaluation of serum protein binding by using in vitro pharmacological activity for the effective pharmacokinetics profiling in drug discovery.

The establishment of a new index for the profile of serum protein binding was analyzed theoretically. The in vitro pharmacological activity ratio of the inhibition constant in the absence of serum protein to that in its presence (activity ratio), which represents the extent of specific binding to serum protein, was suggested as the new index. To clarify the usefulness of the activity ratio, theoretical analysis by the activity ratio for 3% human serum albumin was examined in comparison with conventional methods of equilibrium dialysis. In-house very late antigen-4 antagonists were used as model compounds, whose pharmacokinetics were strongly influenced by serum protein binding. Although the theoretical and actual unbound fractions were similar, the latter tended to be slightly lower than the former. This small difference was considered to correspond to nonspecific binding. These results suggested that the specific and nonspecific binding could be discriminated by comparing the activity ratio data with those of conventional methods. Moreover, the activity ratio was suggested to be useful in profiling the influence of protein binding on pharmacokinetics. In conclusion, it was considered that the activity ratio could avoid the risk of misleading interpretation by nonspecific binding in pharmacokinetics/pharmacological activity. Moreover, the activity ratio was considered to be valuable as one of the useful parameters in pharmacokinetics profiling and as a tool of rational drug design for drug discovery.

MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 4: Addressing the problem of poor stability due to photoisomerization of an acrylic acid moiety.

Exchange of the ethylene tether in a series of pyridopyrimidine-based MexAB-OprM specific efflux pump inhibitors to an amide bond stabilized the olefin of the acrylic acid moiety, preventing facile photoisomerization to the Z-isomer. Furthermore, the activity was drastically improved in the amide tether variants, providing extremely potent acrylic acid and vinyl tetrazole analogues.