Potency, drug discovery programs

The complex and often uncertain outcome of drug discovery and development processes requires the simultaneous optimization of several properties. It has now long been recognized that favorable potency and selectivity characteristics are not the sole hallmarks of a successful drug discovery program, nor is the safety profile considered to be the only hurdle to be overcome, although it is of paramount importance. The ability to prospectively predict the pharmacokinetics of new chemical entities in humans is a powerful means by which one can select for further development only those compounds with the potential to be successful therapeutic agents. 

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. 

The isolation of the benzolactone enamide salicylihalamide A 17101 (Scheme 6.1 Part 2) was guided by the NCI s Drug Discovery Research and Development, Developmental Therapeutics Program screen for differential cytotoxicity, which showed that the Australian sample of Haliclona possessed a unique 60 cell line profile. Nanomolar potency was evident in the melanoma cell lines (GI50 = 7 nM) and a COMPARE analysis of the 60 cell line data indicated vascular ATPase (V-ATPase) activity potential. Further study of this structure class determined that salicylihalamide A is equipotent to the V-ATPase standards bafilomycin A and concanamycin A,273 but unlike these standards, selectively inhibits mammalian V-ATPases. 

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