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

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.