The influence of lead discovery strategies on the properties of drug candidates

被引:473
作者
Keserue, Gyoergy M. [1 ]
Makara, Gergely M. [2 ]
机构
[1] Gedeon Richter, Discovery Chem, H-1475 Budapest, Hungary
[2] Merck Res Labs, Dept Target Validat, Rahway, NJ 07065 USA
关键词
BINDING; SOLUBILITY; GENERATION; INHIBITORS; EFFICIENCY;
D O I
10.1038/nrd2796
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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.
引用
收藏
页码:203 / 212
页数:10
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