Optimization in Drug Discovery

ISBN-13: 9781617374999 / Angielski / Miękka / 2010 / 420 str.

Zhengyin Yan; Gary W. Caldwell

Opis

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.

Recenzje

"This book covers most of the currently used techniques in lead optimization with respect to ADME and safety profiles. . .would be very useful addition to the library of any drug scientist interested in an introduction to these important methods. Each chapter treats its topic in a concise manner and provides ample references to lead the reader to more detailed information."-Doody's Health Sciences Book Review Journal

"...very useful technically...invaluable to those changing roles or joining a pharmaceutical company, it is also very helpful for scientists in the biotech industry who are new to drug discovery." - Immunology News

"The book provides a wealth of relevant information...the tome is neatly designed, well constructed and easy to read." - ISSX Newsletter

"...a useful reference handbook for in vitro ADMET assays." - ChemBioChem

Spis treści

pKa, Solubility and Lipophilicity: Assessing Physicochemical Properties of Lead Compounds Yushen Guo and Hong Shen Use of Caco-2 Cell Monolayers to Study Drug Absorption and Metabolism Ming Hu, Jie Ling, Huimin Lin, and Jun Chen Absorption Screening Using the PAMPA Approach Jeffrey A. Ruell and Alex Avdeef In Situ Single-Pass Perfused Rat Intestinal Model for Absorption and Metabolism Eun Ju Jeong, Yan Liu, Huimin Lin, and Ming Hu In Vitro Permeation Study With Bovine Brain Microvessel Endothelial Cells Seong-Hee Park, Sung-Hack Lee, Yaming Su, and Patrick J. Sinko An Enzymatic Microplate Assay for Testing P-Glycoprotein Substrates and Inhibitors S. Orlowski, J. Nugier, and Eric Ezan Evaluation of Drug-Transporter Interactions Using In Vitro Cell Models Yaming Su and Patrick J. Sinko Plasma Protein-Binding Methods in Drug Discovery Lucinda H. Cohen Isothermal Titration Calorimetry Characterization of Drug-Binding Energetics to Blood Proteins Gary W. Caldwell and Zhengyin Yan Metabolic Stability Assessed by Liver Microsomes and Hepatocytes David C. Ackley, Kevin T. Rockich, and Timothy R. Baker In Vitro Drug Metabolite Profiling Using Hepatic S9 and Human Liver Microsomes Wu-Nan Wu and Linda A. McKown In Vitro Identification of UDP-glucuronosyltransferases Involved in Drug Metabolism Michael H. Court In Vitro CYP Induction in Human Hepatocytes Daniel R. Mudra and Andrew Parkinson High-Throughput Screening of Human Cytochrome P450 Inhibitors Using Fluorometric Substrates: Methodology for 25 Enzyme/Substrate Pairs David M. Stresser Evaluation of Cytochrome P450 Inhibition in Human Liver Microsomes Zhengyin Yan and Gary W. Caldwell Identification of CYP Mechanism-Based Inhibitors Amin A. Nomeir, Jairam Palamanda, and Leonard Favreau Detection of DNA Adducts by 32P-Postlabeling Analysis Naomi Suzuki, Padmaja M. Prabhu, and Shinya Shibutani Covalent DNA Adduct Formation Mediated by Cytochrome P450 Marie Stiborová Application of In Vitro Comet Assay for Genotoxicity Testing Bojana Zegura and Metka Filipic Assessing DNA Damage Using a Reporter Gene System Xuming Jia and Wei Xiao Improvement of the Ames Test Using Human Liver S9 Preparation Atsushi Hakura, Satoshi Suzuki, and Tetsuo Satoh Screening for Chemical Mutagens Using the Mouse Lymphoma Assay Tao Chen and Martha M. Moore A High-Throughput Binding Assay for HERG Keith Finlayson and John Sharkey In Vitro Drug Metabolism: Thiol Conjugation Wei Tang and Randy R. Miller In Vitro Screening Assay of the Reactivity of Acyl Glucuronides Sébastien Bolze Index

Blurb

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.