N-{3-[2-(4-Alkoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynyl}carboxy Derivatives as Acetyl-CoA Carboxylase Inhibitors-Improvement of Cardiovascular and Neurological Liabilities via Structural Mod
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- 作者：Yu Gui Gu ; Moshe Weitzberg ; Richard F. Clark ; Xiangdong Xu ; Qun Li ; Nathan L. Lubbers ; Yi Yang ; David W. A. Beno ; Deborah L. Widomski ; Tianyuan Zhang ; T. Matthew Hansen ; Robert F. Keyes ; Jeffrey F. Wa
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：March 8, 2007
- 年：2007
- 卷：50
- 期：5
- 页码：1078 - 1082
- 全文大小：187K
- 年卷期：v.50,no.5(March 8, 2007)
- ISSN：1520-4804
文摘
A preliminary safety evaluation of ACC2 inhibitor 1-(S) revealed serious neurological and cardiovascularliabilities of this chemotype. A systematic structure-toxicity relationship study identified the alkyne linkeras the key motif responsible for these adverse effects. Toxicogenomic studies in rats showed that 1-(R) and1-(S) induced gene expression patterns similar to that seen with several known cardiotoxic agents such asdoxorubicin. Replacement of the alkyne with alternative linker groups led to a new series of ACC inhibitorswith drastically improved cardiovascular and neurological profiles.