Optimization in Drug Discovery

Recent analyses of drug attrition rates reveal that a significant number of drug candidates fail in the later stage of clinical development owing to absorption, distribution, metabolism, elimination (ADME), and toxicity issues. Lead optimization in drug discovery, a process attempting to uncover and correct these defects of drug candidates, is highly beneficial in lowering the cost and time to develop therapeutic drugs by reducing drug candidate failures in development. At present, parallel synthesis combining with high-throughput screening has made it easier to generate highly potent compounds (i. e. , hits). However, to be a potential drug, a hit must have drug-like characteristics in addition to potency, which include optimal physicochemical properties, reasonable ph- macokinetic parameters, and good safety profiles. Therefore, research tools must be available in drug discovery to rapidly screen for compounds with favorable drug-like properties, and thus adequate resources can be directed to projects with high potential. Optimization in Drug Discovery: In Vitro Methods is a compilation of detailed experimental protocols necessary for setting up a variety of assays important in compound evaluation. A total of 25 chapters, contributed by many experts in their research areas, cover a wide spectrum of subjects including physicochemical properties, abso- tion, plasma binding, metabolism, drug interactions, and toxicity. A good pharmacokinetic profile has long been recognized as an imp- tant drug-like characteristic. Pharmacokinetic parameters are affected by many properties of drug molecules such as physicochemical nature, abso- tion, metabolic stability, and so on.

Includes supplementary material: sn.pub/extras

Klappentext
Although parallel synthesis combined with high-throughput screening has made it easier to generate highly potent drug candidates, many of these compounds never make the grade because they either prove to be unsafe or lack the necessary physicochemical and pharmacokinetic properties. In Optimization in Drug Discovery: In Vitro Methods, a panel of researchers and experts from leading universities and major pharmaceutical companies from all over the world provide proven solutions to this expensive problem with a collection of cutting-edge experimental protocols for early in vitro evaluation of new chemical entities (NCE). These readily reproducible assays measure such critical parameters as physicochemical properties, adsorption, plasma binding, metabolism, drug interactions, and toxicity. All protocols follow the successful Methods in Molecular Biology™ series format, each one offering step-by-step laboratory instructions, an introduction outlining the principle behind the technique, lists of equipment and reagents, and tips on troubleshooting and avoiding known pitfalls.
Comprehensive and highly practical, Optimization in Drug Discovery: In Vitro Methods systematically collects and describes the key methods for uncovering-as early in the discovery stage as possible-those defects that can eliminate candidate drugs from preclinical and clinical development.

Inhalt
pKa, Solubility, and Lipophilicity.- Use of Caco-2 Cell Monolayers to Study Drug Absorption and Metabolism.- Absorption Screening Using the PAMPA Approach.- In Situ Single-Pass Perfused Rat Intestinal Model for Absorption and Metabolism.- In Vitro Permeation Study With Bovine Brain Microvessel Endothelial Cells.- An Enzymatic Microplate Assay for Testing P-Glycoprotein Substrates and Inhibitors.- Evaluation of Drug-Transporter Interactions Using In Vitro Cell Models.- Plasma Protein-Binding Methods in Drug Discovery.- Isothermal Titration Calorimetry Characterization of Drug-Binding Energetics to Blood Proteins.- Metabolic Stability Assessed by Liver Microsomes and Hepatocytes.- In Vitro Drug Metabolite Profiling Using Hepatic S9 and Human Liver Microsomes.- In Vitro Identification of UDP-Glucuronosyltransferases (UGTs) Involved in Drug Metabolism.- In Vitro CYP Induction in Human Hepatocytes.- High-Throughput Screening of Human Cytochrome P450 Inhibitors Using Fluorometric Substrates.- Evaluation of Cytochrome P450 Inhibition in Human Liver Microsomes.- Identification of CYP Mechanism-Based Inhibitors.- Detection of DNA Adducts by 32P-Postlabeling Analysis.- Covalent DNA Adduct Formation Mediated by Cytochrome P450.- Application of In Vitro Comet Assay for Genotoxicity Testing.- Assessing DNA Damage Using a Reporter Gene System.- Improvement of the Ames Test Using Human Liver S9 Preparation.- Screening for Chemical Mutagens Using the Mouse Lymphoma Assay.- A High-Throughput Binding Assay for HERG.- In Vitro Drug Metabolism.- In Vitro Screening Assay of the Reactivity of Acyl Glucuronides.