Lipinski C A, Lombardo F, Dominy B W, Feeney P J
Central Research Division, Pfizer Inc., Groton, CT 06340, USA.
Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26. doi: 10.1016/s0169-409x(00)00129-0.
Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP > 4.15). Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described. Turbidimetric solubility measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era. In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements.
本文描述了在药物研发过程中用于评估溶解度和渗透性的实验方法和计算方法。在药物发现阶段，“五规则”预测，当氢键供体超过5个、氢键受体超过10个、分子量（MWT）大于500且计算得到的Log P（CLogP）大于5（或MlogP > 4.15）时，药物更有可能吸收差或渗透差。文中描述了基于规则的森口Log P（MLogP）计算的计算方法。介绍了比浊法溶解度测量并将其应用于已知药物。与高通量筛选（HTS）前时代的先导化合物相比，高通量筛选（HTS）得到的先导化合物往往具有更高的分子量和Log P以及更低的比浊法溶解度。在药物开发阶段，溶解度计算侧重于精确值预测，但由于多晶型现象而具有挑战性。本文对线性自由能关系和Log P方法的最新研究进行了批判性综述。当与实验热力学溶解度测量相结合时，在密切相关的类似物系列中可以做出有用的预测。
