Hit and Lead Profiling: Identification and Optimization of Drug-like Molecules, Volume 43

The only reference on current methods to generate pharmacokinetic and safety profiles of drug candidates, as well as how they must be balanced against one other for the best selection of candidates for further development. Following a brief introduction to the necessities of filtering and risk assessment of potential new drug molecules before actual drug development, the two equally important aspects of pharmacological (ADME) and safety (toxicity) profiling are covered in separate parts. The ADME section covers the profiling of basic physicochemical parameters, such as solubility and permeability, as well as more complex traits, such as the likelihood of drug-drug interactions, metabolic clearance and protein binding properties. The toxicology part addresses, among others, recent advances in early genetic toxicity testing, bioactivation screening, organ-specific toxicity assays for liver, heart, kidney and blood, as well as profiling for autoimmune reactions. By addressing both drug efficiency and drug safety, this modern practical reference shows readers how each individual aspect figures in shaping the key decisions on which the entire drug development process hinges. In short, this is a complete toolbox for assessing the risk/benefit ratio for any novel compound during the early drug development stages, using both in vitro and in silico methods. Both editors are based at one of the leading research-driven pharmaceutical companies, and the authors have been recruited from numerous other global players in the field. Invaluable know-how for every medicinal chemist and drug developer.Content: Chapter 1 Process Logistics, Testing Strategies and Automation Aspects (pages 1–24): Hansjoerg Haas, Robert S. DeWitte, Robert Dunn?Dufault and Andreas Stelzer Chapter 2 Prediction of Drug?Likeness and its Integration into the Drug Discovery Process (pages 25–40): Ansgar Schuffenhauer and Meir Glick Chapter 3 Integrative Risk Assessment (pages 41–67): Prof., Dr. Bernard Faller and Dr. Laszlo Urban Chapter 4 Solubility and Aggregation (pages 69–90): William H. Streng Chapter 5 In Silico Tools and In Vitro HTS Approaches to Determine Lipophilicity During the Drug Discovery Process (pages 91–116): Sophie Martel, Vincent Gasparik and Pierre?Alain Carrupt Chapter 6 Membrane Permeability – Measurement and Prediction in Drug Discovery (pages 117–143): Kiyohiko Sugano, Lourdes Cucurull?Sanchez and Joanne Bennett Chapter 7 Drug Metabolism and Reactive Metabolites (pages 145–163): Alan P. Watt Chapter 8 Drug–Drug Interactions: Screening for Liability and Assessment of Risk (pages 165–196): Ruth Hyland, R. Scott Obach, Chad Stoner, Michael West, Michael R. Wester, Kuresh Youdim and Michael Zientek Chapter 9 Plasma Protein Binding and Volume of Distribution: Determination, Prediction and Use in Early Drug Discovery (pages 197–220): Franco Lombardo, R. Scott Obach and Nigel J. Waters Chapter 10 Putting it All Together (pages 221–240): Pamela Berry, Neil Parrott, Micaela Reddy, Pascale David?Pierson and Thierry Lave Chapter 11 Genetic Toxicity: In Vitro Approaches for Hit and Lead Profiling (pages 241–271): Richard M Walmsley and Nicholas Billinton Chapter 12 In Vitro Safety Pharmacology Profiling: An Important Tool to Decrease Attrition (pages 273–295): Jacques Hamon and Steven Whitebread Chapter 13 Knowledge?Based and Computational Approaches to In Vitro Safety Pharmacology (pages 297–322): Josef Scheiber, Andreas Bender, Kamal Azzaoui and Jeremy Jenkins Chapter 14 Discovery Toxicology Screening: Predictive, In Vitro Cytotoxicity (pages 323–343): Peter J. O'Brien Chapter 15 Predicting Drug?Induced Hepatotoxicity: In Vitro, In Silico and In Vivo Approaches (pages 345–385): Jinghai J. Xu, Amit S. Kalgutkar, Yvonne Will, James Dykens, Elizabeth Tengstrand and Frank Hsieh Chapter 16 Should Cardiosafety be Ruled by hERG Inhibition? Early Testing Scenarios and Integrated Risk Assessment (pages 387–413): Dimitri Mikhailov, Martin Traebert, Qiang Lu, Steven Whitebread and William Egan Chapter 17 Hematotoxicity: In Vitro and Ex Vivo Compound Profiling (pages 415–437): David Brott and Francois Pognan Chapter 18 Profiling Adverse Immune Effects (pages 439–469): Wim H. De Jong, Raymond Pieters, Kirsten A Baken, Rob J. Vandebriel, Jan?Willem Van Der Laan and Henk Van Loveren Chapter 19 In Vitro Phototoxicity Testing: A Procedure Involving Multiple Endpoints (pages 471–494): Laurent Marrot and Jean?Roch Meunier

The enormous cost incurred when a candidate drug fails in a clinical trial because of poor pharmacological parameters or severe side effects makes it imperative to screen for "safe" drugs in the very early stages of drug development. Various biochemical and other in vitro assays are thus used in conjunction with the analysis of physicochemical properties of the potential drug molecules, enabling an informed selection of drug development candidates before they enter clinical trials.

By addressing both drug efficiency and drug safety, this modern practical reference shows how each individual aspect figures in shaping the key decisions on which the entire drug development process hinges. The result is a complete toolbox for assessing the risk/benefit ratio for any novel compound, using both in vitro and in silico methods.

Following a brief introduction to the necessities of filtering and risk assessment, the two equally important aspects of pharmacological (ADME) and safety (toxicity) profiling are covered in separate parts. The whole of the fourth and final part is devoted to organ-specific toxicity assays for the liver, heart, kidney and blood, as well as profiling for autoimmune reactions.

Invaluable know-how for every medicinal chemist and drug developer.

By addressing both drug efficiency and drug safety, this modern practical reference shows how each aspect shapes the key decisions for assessing the risk/benefit ratio of any novel compound during the early drug development stages, using both in vitro and in silico methods.