Amine promiscuity and toxicology analysis

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• 作者：Esther C.Y. Lee^a ; ^{esther.lee2@pfizer.com} ; Gregory Steeno^b ; Anne Mai Wassermann^d ; Liying Zhang^c ; Falgun Shah^c ; David A. Price^a
• 关键词：Amines ; Pharmacological profiling ; Promiscuity ; Toxicology ; Half-life
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：27
• 期：3
• 页码：653-657
• 全文大小：959 K
• 卷排序：27

文摘

Drug discovery programs often face challenges to obtain sufficient duration of action of the drug (i.e. seek longer half-lives). If the pharmacodynamic response is driven by free plasma concentration of the drug then extending the plasma drug concentration is a valid approach. Half-life is dependent on the volume of distribution, which in turn can be dependent upon the ionization state of the molecule. Basic compounds tend to have a higher volume of distribution leading to longer half-lives. However, it has been shown that bases may also have higher promiscuity. In this work, we describe an analysis of in vitro pharmacological profiling and toxicology data investigating the role of primary, secondary, and tertiary amines in imparting promiscuity and thus off-target toxicity. Primary amines are found to be less promiscuous in in vitro assays and have improved profiles in in vivo toxicology studies compared to secondary and tertiary amines.