N-{3-[2-(4-Alkoxyphenoxy) thiazol-5-yl]-1-methylprop-2-ynyl} carboxy derivatives as acetyl-CoA carboxylase inhibitors improvement of cardiovascular and …

YG Gu, M Weitzberg, RF Clark, X Xu, Q Li…

Index: Gu, Yu Gui; Weitzberg, Moshe; Clark, Richard F.; Xu, Xiangdong; Li, Qun; Lubbers, Nathan L.; Yang, Yi; Beno, David W. A.; Widomski, Deborah L.; Zhang, Tianyuan; Hansen, T. Matthew; Keyes, Robert F.; Waring, Jeffrey F.; Carroll, Sherry L.; Wang, Xiaojun; Wang, Rongqi; Healan-Greenberg, Christine H.; Blomme, Eric A.; Beutel, Bruce A.; Sham, Hing L.; Camp, Heidi S. Journal of Medicinal Chemistry, 2007 , vol. 50, # 5 p. 1078 - 1082

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Citation Number: 18

Abstract

A preliminary safety evaluation of ACC2 inhibitor 1-(S) revealed serious neurological and cardiovascular liabilities of this chemotype. A systematic structure-toxicity relationship study identified the alkyne linker as the key motif responsible for these adverse effects. Toxicogenomic studies in rats showed that 1-(R) and 1-(S) induced gene expression patterns similar to that seen with several known cardiotoxic agents such as doxorubicin. ...