2. Academic Validation
  3. 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

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

  • J Med Chem. 2007 Mar 8;50(5):1078-82. doi: 10.1021/jm070035a.
Yu Gui Gu 1,  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
Affiliations

Affiliation

  • 1 Global Pharmaceutical Research and Development, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064, USA. [email protected]
PMID: 17298049 DOI: 10.1021/jm070035a
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. Replacement of the alkyne with alternative linker groups led to a new series of ACC inhibitors with drastically improved cardiovascular and neurological profiles.

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