Compound attrition

Examples of the application of strategies based on increasing LLE or LipE and optimizing physicochemical properties as key components of medicinal chemistry programs that delivered clinical development candidates have begun to be described in the last year or so. It remains to be seen whether the hoped for reduction in compound attrition that this approach seeks to achieve will be realized, as it is early days. 

FIGURE 7.1 Major reasons for compound attrition during clinical studies (1991-2000). (Source Adapted from Kola, I. and Landis, J. Nat. Rev. Drug Dis., 2004, 3, 711. With permission.)... 

The effort was very successful and the results were documented by Kola and Landis1 who stated that the situation changed and that fewer than 10% of current clinical failures arose from PK problems. Figure 7.1 portrays this shift in reasons for compound attrition. The increased emphasis on early ADME/PK screening resulted in a significant change in reasons for compound failure from Phase I to FDA approval—PK is no longer a major reason. 

Physicochemical profiling at the early discovery stage is important in the pharmaceutical industry because poor bioavailability is a leading factor in compound attrition. The ability to rapidly measure absorption properties such as solubility, log P, and log D allows promising compounds to quickly pass into exploratory development. 

A number of ancillary issues must also be addressed in addition to those dealt with in the compound selection procedure itself. One of these is compound attrition each year, about 1% of the compounds in a given collection are, for a variety of reasons, no longer available. Some of these maybe rare or unusual compounds that are difficult to replace. If and how these are replaced is a subject for discussion that will not, however, be dealt... 

The current emphasis is on speed to market, and therefore investment decisions have to take into account the high levels of compound attrition in the industry. When there are exciting results from clinical trials, programs get accelerated, and there is then a danger of being locked into chemical routes and processes that are sub-optimal from an environmental point of view. Measures tliat can be taken to counter this pressure include ... 

Figure 1 illustrates the process of drug discovery, which involves a multidisciplinary approach with a constant influx of new technologies and output of information that results in a lower compound attrition rate and compounds with improved druglike characteristics. Ultimately, this entire process comes together to produce a greater number of better drugs to treat disease. 

FIG U RE 1.1 Schematic chart showing the effect of compound attrition in the drug discovery process from compound libraries to drug approval. The x-axis is the stage or point in the process. The y-axis is the number of compounds at that point. 

This raises the key test of target validation. Does a compound that has the appropriate potency, selectivity, and ADME properties, that is active in "predictive" animal models, and is free of other systems toxicology work in the targeted human disease state This is the ultimate test of a target-based drug discovery program. With the considerable compound attrition rates in moving from animals to diseased humans, this has not proven to be a predictable transition. A case in point is that of the NKl receptor activated by the peptide, substance P. 

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