Current trends in lead discovery: Are we looking for the appropriate properties?

The new drug disc very paradigm is based on high-throughput technologies, both with respect to synthesis and screening. The progression HTS hits --> lead series --> candidate drug marketed drug appears to indicate that the probability of reaching launched status is one in a million. This has shifted the focus from good quality candidate drugs to good quality leads. We examined the current trends in lead discovery by comparing MW ( molecular weight), LogP (octanol/water partition coefficient, estimated by Kowwin [17]) and LogSw ( intrinsic water solubility, estimated by Wskowwin [18]) for the following categories: 62 leads and 75 drugs [ 11]; compounds in the development phase (I, II, III and launched), as indexed in MDDR; and compounds indexed in medicinal chemistry journals [ref. 20], categorized according to their biological activity. Comparing the distribution of the above properties, the 62 lead structures show the lowest median with respect to MW (smaller) and LogP (less hydrophobic), and the highest median with respect to LogSw (more soluble). By contrast, over 50% of the medicinal chemistry compounds with activities above 1 nanomolar have MW > 425, LogP > 4.25 and LogSw < - 4.75, indicating that the reported active compounds are larger, more hydrophobic and less soluble when compared to time-tested quality leads. In the MDDR set, a progressive constraint to reduce MW and LogP, and to increase LogSw, can be observed when examining trends in the developmental sequence: phase I, II, III and launched drugs. These trends indicate that other properties besides binding affinity, e.g., solubility and hydrophobicity, need to be considered when choosing the appropriate leads.