Identification, Synthesis, and Biological Evaluation of the Metabolites of 3-Amino-6-(3鈥?aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11-(6H)dione (AM6鈥?6), a Promising Rexinoid Le

详细信息    查看全文

• 作者：Lian Chen ; Martin Conda-Sheridan ; P. V. Narasimha Reddy ; Andrew Morrell ; Eun-Jung Park ; Tamara P. Kondratyuk ; John M. Pezzuto ; Richard B. van Breemen ; Mark Cushman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 28, 2012
• 年：2012
• 卷：55
• 期：12
• 页码：5965-5981
• 全文大小：712K
• 年卷期：v.55,no.12(June 28, 2012)
• ISSN：1520-4804

文摘

Activation of the retinoid X receptor (RXR), which is involved in cell proliferation, differentiation, and apoptosis, is a strategy for cancer chemotherapy and chemoprevention, and 3-amino-6-(3鈥?aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11-(6H)dione (AM6鈥?6) (3) is among the few RXR ligands known. The presently reported studies of 3 include its binding to human plasma proteins, metabolic stability using human liver microsomes, metabolism by human liver microsomes and hepatocytes, and in vivo disposition in rat serum, liver, and mammary tissue. Compound 3 was 75% bound to human plasma proteins, and its metabolic stability was much greater than propranolol. One phase I metabolite was formed by human liver microsomes, seven phase I and II metabolites were formed by human hepatocytes, and five metabolites were detected in rat serum and liver after oral administration. The putative metabolites predicted using LC-MS-MS were synthesized to confirm their structures and to provide sufficient material for investigation of induction of RXRE transcriptional activity and inhibition of NF魏B.