Navigating CYP1A Induction and Arylhydrocarbon Receptor Agonism in Drug Discovery. A Case History with S1P1 Agonists

详细信息    查看全文

• 作者：Simon J. Taylor ; Emmanuel H. Demont ; James Gray ; Nigel Deeks ; Aarti Patel ; Dung Nguyen ; Maxine Taylor ; Steve Hood ; Robert J. Watson ; Rino A. Bit ; Fiona McClure ; Holly Ashall ; Jason Witherington
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：October 22, 2015
• 年：2015
• 卷：58
• 期：20
• 页码：8236-8256
• 全文大小：660K
• ISSN：1520-4804

文摘

This article describes the finding of substantial upregulation of mRNA and enzymes of the cytochrome P450 1A family during a lead optimization campaign for small molecule S1P₁ agonists. Fold changes in mRNA up to 10鈥?00-fold for CYP1A1 in vivo in rat and cynomolgus monkey and up to 45-fold for CYP1A1 and CYP1A2 in vitro in rat and human hepatocytes were observed. Challenges observed with correlating induction in vitro and induction in vivo resulted in the implementation of a short, 4 day in vivo screening study in the rat which successfully identified noninducers. Subtle structure鈥揳ctivity relationships in this series of S1P₁ agonists are described extending beyond planarity and lipophilicity, and the impact and considerations of AhR and CYP1A induction in the context of drug development are discussed.