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 08;50(5):1078-82
Date
02/15/2007Pubmed ID
17298049DOI
10.1021/jm070035aScopus ID
2-s2.0-33847792163 (requires institutional sign-in at Scopus site) 33 CitationsAbstract
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.
Author List
Gu YG, Weitzberg M, Clark RF, Xu X, Li Q, Lubbers NL, Yang Y, Beno DW, Widomski DL, Zhang T, Hansen TM, Keyes RF, Waring JF, Carroll SL, Wang X, Wang R, Healan-Greenberg CH, Blomme EA, Beutel BA, Sham HL, Camp HSAuthor
Robert Keyes PhD Research Scientist II in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Acetyl-CoA CarboxylaseAdministration, Oral
Animals
Blood Pressure
Gene Expression
Heart Rate
Infusions, Intravenous
Male
Myocardium
Oligonucleotide Array Sequence Analysis
Rats
Rats, Sprague-Dawley
Seizures
Stereoisomerism
Structure-Activity Relationship
Thiazoles
