Diversity measures for enhancing ADME admissibility of combinatorial libraries

For general screening libraries, structural diversity descriptors and drug- likeness indicators still do not guarantee the in vivo bioavailability for the candidates, which is considered a major bottleneck in drug development. Early prediction of pharmacokinetics (log P, log D), metabolism, and toxic ity makes it possible to deal with ADME (adsorption, distribution, metaboli sm, excretion) related diversity as an extension to the classical diversity concepts. It opens several new possibilities for optimization of a discove ry library before doing any experimental. screening. This new diversity con cept is demonstrated on a subset of MeDiverse, which is a diverse collectio n of pharmacologically relevant compounds selected From our in-house librar y. From consideration of the ADME interface in living systems, virtual seco ndary libraries of metabolites and retrometabolites (prodrugs) can be gener ated. These additional libraries readily enhance both the structural and AD ME related diversity. This new opportunity in library design can substantia lly improve the success rate for in vivo lead generation from in vitro hits .