The influence of lead discovery strategies on the properties of drug candidates.
Despite the widespread acceptance of guidelines related to desirable physicochemical properties of potential small-molecule drugs, key properties - such as lipophilicity - of recently developed clinical candidates and advanced lead compounds have been shown to differ significantly from those of historical leads and drugs. By analysing the physicochemical properties of a large database of hits and corresponding leads identified in the past decade, we show that this undesirable phenomenon can be traced back to the nature of high-throughput screening hits and hit-to-lead optimization practices. Conceptual and organizational adjustments may be required to enable a smooth lead-evolution process that reduces the chance of high compound-related attrition in clinical trials.
Keserü
György M
GM
Discovery Chemistry, Gedeon Richter, PO Box 27, H-1475 Budapest, Hungary. gy.keseru@richter.hu
Makara
Gergely M
GM
D002626:Chemistry, Pharmaceutical; D002986:Clinical Trials as Topic; D016208:Databases, Factual; D055808:Drug Discovery; D004345:Drug Industry / Q000458:organization & administration*; D017408:Guidelines as Topic; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry*
D004364:Pharmaceutical Preparations