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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2007 Mar 08; Vol. 50 (5), pp. 1078-82. Date of Electronic Publication: 2007 Feb 14. - Publication Year :
- 2007
-
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.
- Subjects :
- Administration, Oral
Animals
Gene Expression drug effects
Infusions, Intravenous
Male
Myocardium metabolism
Oligonucleotide Array Sequence Analysis
Rats
Rats, Sprague-Dawley
Stereoisomerism
Structure-Activity Relationship
Thiazoles adverse effects
Thiazoles chemistry
Acetyl-CoA Carboxylase antagonists & inhibitors
Blood Pressure drug effects
Heart Rate drug effects
Seizures chemically induced
Thiazoles chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 50
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 17298049
- Full Text :
- https://doi.org/10.1021/jm070035a