Drug, drugs project

This type of analysis is now well established and has been used in many drug discovery projects over the past fifteen years. Examples include HIV protease inhibitors [13], anti-influenza drugs [14], isoform-selective ligands for the estrogen receptor [15], and many more. 

This last section presents some practical applications of conformational analysis in drug discovery projects. To illustrate the importance of conformational energy calculations we draw mainly on examples taken from our experience and chosen to reflect different scales of problems that can be addressed. 

The NDA Pipeline. The NDA Pipeline s database [94] of more than 7000 drug development projects is available as a web-delivered, searchable information service that is updated each week. A copy of the annual book, an information service from FDC... 

Since most drug discovery projects deal with very sparingly soluble compounds, the usual CE sample concentration would lead to precipitation. The handling of real dmg candidate molecules is poorly developed in CE applications, in comparison to the most robust potentiometric method. 

There are several approaches to estimating absorption using in vitro methods, notably Caco-2 and MDCK cell-based methods or using methods that assess passive permeability, for example the parallel artificial membrane permeation assay (PAMPA) method. These are reviewed elsewhere in this book. The assays are very useful, and usually have an important role in the screening cascades for drug discovery projects. However, as discussed below, the cell-based assays are not without their drawbacks, and it is often appropriate to use ex vivo and/or in vivo absorption assays. 

Phospholipidosis is an excessive intracellular accumulation of phospholipids and drug, which is normally reversible after discontinuation of drug treatment. Currently, it is thought that phospholipidosis alone is not toxic per se, but because some compounds cause concurrent phospholipidosis and organ toxicity, avoidance of the issue in drug discovery projects seems prudent [74]. Fortunately, there are clear links between phospholipidosis and physical properties, especially lipophilicity, basicity, and amphiphilicity [75] which allow for good prediction of the risk. 

Many advances have been made in computational ADME modeling. For many ADME properties, models now exist which provide reasonably good predictive quality and can be deployed to aid medicinal chemists in drug discovery projects. 

CDP (1980) Coronary Drug Project Research Group. Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project. N Engl J Med 303 1038-1041... 

The study by Prentis et al. [4] included an analysis of 198 NCEs, developed between 1964 and 1985 by British pharmaceutical companies but had not been marketed for reasons presented in Figure 1.1. Kennedy [5] further analyzed these data and noticed that a high number of anti-infective drug development projects were all terminated... 

Criteria for Inception of a Medicinal Chemistry-Led Drug Discovery Project... 

Specific Drug Discovery Project Goals for a Small Molecule NME... 

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