Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success

被引:3174
作者
Lovering, Frank [1 ]
Bikker, Jack [2 ]
Humblet, Christine [3 ]
机构
[1] Wyeth Res, Chem Sci, Cambridge, MA 02140 USA
[2] Wyeth Res, Chem Sci, Pearl River, NY 10965 USA
[3] Wyeth Res, Chem Sci, Monmouth Jct, NJ 08543 USA
关键词
ORAL BIOAVAILABILITY; MOLECULAR COMPLEXITY; DRUG DISCOVERY; SOLUBILITY; CHEMISTRY; SET;
D O I
10.1021/jm901241e
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The medicinal chemistry community has become increasingly aware of the value of tracking calculated physical properties such as molecular weight, topological polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. We hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose molecules to fail by steering discovery efforts toward achiral, aromatic compounds. We have proposed two simple and interpretable measures of the complexity of molecules prepared as potential drug candidates. The first is carbon bond saturation as defined by fraction sp(3) (Fsp(3)) where Fsp(3) = (number of sp(3) hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the molecule. We demonstrate that both complexity (as measured by Fsp(3)) and the presence of chiral centers correlate with success its compounds transition from discovery, through clinical testing, to drugs. In an attempt to explain these observations, we further demonstrate that saturation correlates with solubility, an experimental physical property important to success in the drug discovery setting.
引用
收藏
页码:6752 / 6756
页数:5
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