jm070035a_si_001.pdf (105.9 kB)
Download file

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 Modifications

Download (105.9 kB)
journal contribution
posted on 08.03.2007, 00:00 by 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. Waring, Sherry L. Carroll, Xiaojun Wang, Rongqi Wang, Christine H. Healan-Greenberg, Eric A. Blomme, Bruce A. Beutel, Hing L. Sham, Heidi S. Camp
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. Replacement of the alkyne with alternative linker groups led to a new series of ACC inhibitors with drastically improved cardiovascular and neurological profiles.