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
  • 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.