Improving the Odds of Success in Drug Discovery: Choosing the Best Compounds for in Vivo Toxicology Studies

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• 作者：Travis T. Wager ; Bethany L. Kormos ; Joseph T. Brady ; Yvonne Will ; Michael D. Aleo ; Donald B. Stedman ; Max Kuhn ; Ramalakshmi Y. Chandrasekaran
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 12, 2013
• 年：2013
• 卷：56
• 期：23
• 页码：9771-9779
• 全文大小：689K
• 年卷期：v.56,no.23(December 12, 2013)
• ISSN：1520-4804

文摘

A set of molecules that advanced into exploratory animal toxicology studies (two species) was examined to determine what properties contributed to success in these safety studies. Compounds were rigorously evaluated across numerous safety end points and classified as 鈥減ass鈥?if a suitable in vivo therapeutic index (TI) was achieved for advancement into regulatory toxicology studies. The most predictive end point contributing to compound survival was a predicted human efficacious concentration (C_eff) of 鈮?50 nM (total drug) and 鈮?0 nM (free drug). This trend held across a wide range of CNS modes of action, encompassing targets such as enzymes, G-protein-coupled receptors, ion channels, and transporters.