System suitability potency

Integrated systems suitable for processing the sometimes quite complex workflows more easily or automatically and to optimize new compounds in parallel for their potency, selectivity, and ADMET profile have to be developed. The reliability of the in silico models will be improved and their scope for predictions will be broader as soon as more reliable experimental data are available. However, there is the paradox of predictivity versus diversity. The greater the chemical diversity in a dataset. 

The QSARs for the potency of the active aromatic amines in Salmonella typhimurium were not suitable to differentiate the inactives from the actives, and appropriate QSAR models were derived. The QSAR models specific for the separation were based on electronic and steric terms, and hydrophobicity was not found to be significant (Benigni et al., 1998). This result is analogous to that obtained for the rodent carcinogenicity of amines (see above), and provides further evidence of the similarity of the mechanisms of action in Salmonella and rodents. This similarity obviously applies only to the first steps of the process by which the aromatic amines provoke cancer on one side (rodents), and mutations on the other side (bacteria). Once the initial insult to the cells has occurred, the process follows different pathways in the two biological systems the strength of the QSAR model is that it is able to describe quantitatively the first step, which appears to be rate limiting in both systems. 

Transdermal administration of fentanyl has been extensively reviewed (44). In systemic availability studies, 92% of the fentanyl dose delivered from the transdermal therapeutic system into the skin reached the systemic circulation as unchanged unmetabolized fentanyl (41). Morphine, codeine, and hydromorphone are not good candidates for transdermal administration. Pethidine has a high transdermal permeability but poor analgesic potency. Besides fentanyl, only sufentanil and buprenor-phine would be suitable opioids for transdermal administration (45). 

As calcitriol is not suitable for any systemic therapy due to the ability to induce hypercalciuria and hypercalcemia in the therapeutically relevant dosage, research was focused on the search of dissociated calcitriols with significantly reduced calcitropic potency. At Schering the induction of hypercalcemia was routinely investigated after administration of the compounds to mice and rats. 

The most suitable method for the quantitative evaluation of the positive inotropic effect of a cardioactive steroid is at present the assessment of its influence on the isometric contraction curve, measiured in isolated papillary muscles. However, to obtain reliable data for the comparison of the inotropic potency of the various cardioactive steroids, it is important to perform the experiments under identical conditions [16]. Because of the variety of test conditions used, it is not easy or it is even impossible to compare the data reported in the literature [17,18]. A comprehensive survey of the structure-activity relationships found in guinea-pig left atria under identical conditions has recently been presented by R. Thomas and coworkers [19]. Therefore, this aspect will be mentioned here only with regard to the two basic risks for misinterpretation of pharmacological data from animal model systems. 

An oral/intravenous pharmacokinetic study in rats indicated low clearance (21% liver blood flow), moderate volume of distribution, and good systemic exposure. The limited oral bioavailability and brain penetration observed in this study provided a platform for further optimization, with good molecular properties and a PSA below 70. However, a suitable compound from further development would require increased potency, solubility, and a clear hERG profile. 

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