Antitargets and Drug Safety (Methods and Principles in Medicinal Chemistry)
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With its focus on emerging concerns of kinase and GPCR-mediated antitarget effects, this vital reference for drug developers addresses one of the hot topics in drug safety now and in future.
Divided into three major parts, the first section deals with novel technologies and includes the utility of adverse event reports to drug discovery, the translational aspects of preclinical safety findings, broader computational prediction of drug side-effects, and a description of the serotonergic system. The main part of the book looks at some of the most common antitarget-mediated side effects, focusing on hepatotoxicity in drug safety, cardiovascular toxicity and signaling effects via kinase and GPCR anti-targets. In the final section, several case studies of recently developed drugs illustrate how to prevent anti-target effects and how big pharma deals with them if they occur. The more recent field of systems pharmacology has gained prominence and this is reflected in chapters dedicated to the utility in deciphering and modeling anti-targets. The final chapter is concerned with those compounds that inadvertently elicit CNS mediated adverse events, including a pragmatic description of ways to mitigate these types of safety risks.
Written as a companion to the successful book on antitargets by Vaz and Klabunde, this new volume focuses on recent progress and new classes, methods and case studies that were not previously covered.
bile acid profile after drug administration and also reemphasize the necessity of population analysis due to the large interindividual variability in bile acid disposition in the presence of bile acid transport inhibitors. Construction of a systems pharmacology model revealed that while much is understood qualitatively about bile acid homeostasis, quantitative information essential to the construction of a mechanistic model is still lacking. A sensitivity analysis using human and rat bile acid
the antitarget PKA. The surface of Akt1 near the hinge-binding pyrrolopyrimidine (green) is illustrated in plum, while the truncated cleft in PKA is colored tan; the closure of the PKA cleft is indicated by a black arrow. The bound water is illustrated as a red sphere, and its hydrogen-bonding contacts to Thr211 and Glu228 are shown as orange dashed lines. A partially saturated core was designed in order to access this space. A relatively small number of substitutions around the cyclopentane
quite variable. Lack of reporting, or inadequate reporting of necessary details, is too common, and no reliable estimate of the incidence of drug-induced liver injury can be made from the spontaneous and often isolated, delayed reports that reach publication or official recognition. 5.2.3 Severity of Liver Injury Is Not Measured by Aminotransferase Elevations It is important to appreciate that severity of drug-induced injury to the liver varies from mild asymptomatic injury detectable only by
are expensive, and this factor often limits the size of the assay's validation sets and the number of replicates within an experiment. To improve cost effectiveness, assays conducted on primary hepatocytes are usually reserved for the later stages of lead optimization, when the number of potential candidates has been significantly reduced by prior, less expensive screening methods. Furthermore, it is difficult to replicate experiments conducted with primary hepatocytes. The cells are the product
kinase targets and occasionally to non-kinase targets as well (see Figure 1.2). Figure 1.2 Non-kinase target-related promiscuity of selected kinase inhibitors vandetanib, bosutinib, crizotinib, and sunitinib. The non-kinase-related pharmacological promiscuity of the kinase inhibitors varies broadly and does not reflect on their kinase selectivity. Note that sunitinib (Sutent) is an extremely promiscuous kinase inhibitor. Red: IC50 < 1 �M; yellow: IC50 = 1–10 �M; green: IC50 ≥ 10 �M. Kinase