Baker James A, Altman Michael D, Martin Iain J
Pharmacokinetics, Pharmacodynamics & Drug Metabolism and Modeling & Informatics, MRL, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
ACS Med Chem Lett. 2018 Jul 19;9(8):843-847. doi: 10.1021/acsmedchemlett.8b00259. eCollection 2018 Aug 9.
In early drug discovery, where chiral syntheses may not yet have been elucidated or enantiomeric separation is not feasible, screening of racemates in metabolic stability assays may offer a pragmatic approach. To assess the risk of incorrectly deprioritizing enantiomers due to misclassification of apparent intrinsic clearance (CLint), we evaluated (1) theoretical simulations; (2) literature on enantiomeric CLint differences; (3) historic MSD data; and (4) new data on enantiomers with high eudysmic ratios and low predicted three-dimensional similarity. Overall, the results suggested minimal risk of not progressing an enantiomer due to an appreciably different (>3-fold) racemate CLint.
在早期药物发现阶段，手性合成可能尚未阐明或对映体分离不可行，在代谢稳定性试验中筛选外消旋体可能提供一种实用的方法。为了评估由于表观内在清除率（CLint）分类错误而错误地将对映体排除在优先次序之外的风险，我们评估了：（1）理论模拟；（2）关于对映体CLint差异的文献；（3）历史MSD数据；以及（4）具有高优映比和低预测三维相似性的对映体的新数据。总体而言，结果表明，由于外消旋体CLint明显不同（>3倍）而导致对映体无法推进的风险极小。
