Current Topics in Medicinal Chemistry - Volume 14, Issue 11, 2014

Species difference in drug metabolism and drug toxicity is a well-established phenomenon. As a result, the classical paradigm of preclinical testing of drug candidates in animals may not be appropriate. One preclinical approach to evaluate human drug properties, especially ADMET (absorption, disposition, metabolism, elimination, and toxicity) properties, is to apply in vitro experimental systems with relevant human properties. T Read More

Making reliable predictions of drug metabolites requires detailed knowledge of the chemical reactivity of drug metabolizing enzymes. Cytochrome P450 enzymes (P450s) play an important role in drug metabolism. Numerous adverse drug reactions have been identified that occur as a result of interactions with P450s. These enzymes display complex reactivity and the active oxidizing species is highly reactive and difficult to isolat Read More

Inactivation of human drug-metabolizing cytochrome P450 3A4 (CYP3A4) could lead to serious adverse events such as drug-drug interactions and toxicity. However, when properly controlled, CYP3A4 inhibition may be beneficial as it can improve clinical efficacy of co-administered therapeutics that otherwise are quickly metabolized by CYP3A4. Currently, the CYP3A4 inhibitor ritonavir and its derivative cobicistat are prescribed t Read More

Cheminformatics approaches such as Quantitative Structure Activity Relationship (QSAR) modeling have been used traditionally for predicting chemical toxicity. In recent years, high throughput biological assays have been increasingly employed to elucidate mechanisms of chemical toxicity and predict toxic effects of chemicals in vivo. The data generated in such assays can be considered as biological descriptors of chemical Read More

The analysis of designer drugs in human plasma is highly complex, as most of these drugs are metabolized quickly, and often into multiple products. For novel designer drugs, it is common that reference compounds for these metabolites are unavailable at the time of analysis. Hence, the usage of in silico procedures to accurately predict the chemical structures of these metabolites would be very useful. In this study, t Read More

In the development of new drugs, it is very important to know the effects these may bring to those who consume them. Drugs which act upon certain diseases must not cause toxic side effects on healthy organs. These toxic side effects can be quite varied, i.e. mutagenicity, clastogenicity, teratogenicity, etc., but undoubtedly the mutagenicity officiate in the selection process, during preclinical testing, to advance in clinical t Read More

In this paper, the in vitro microsomal hepatic metabolism of the antiasthmatic prototype LASSBio-448 and the structural identification of its major phase I metabolites were described. Incubation with pooled rat liver microsomes converted LASSBio-448 to the following major metabolites: O-demethyl-LASSBio-448 (M1) and 3,4-dihydroxyphenyl- LASSBio-448 (M2). These metabolites were formed by the dealkylation step of 3,4 Read More

Several non-cardiovascular drugs have been withdrawn from the market due to their inhibition of hERG K+ channels that can potentially lead to severe heart arrhythmia and death. As hERG safety testing is a mandatory FDArequired procedure, there is a considerable interest for developing predictive computational tools to identify and filter out potential hERG blockers early in the drug discovery process. In this study, we aim Read More