Abstract
Acetyl CoA carboxylase (ACC) 2, which catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, has been identified as a potential target for type 2 diabetes and obesity. Small-molecule inhibitors of ACC2 would be expected to reduce de novo lipid synthesis and increase lipid oxidation. Treatment of ob/ob mice with compound A-908292 (S) ({(S)-3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methyl-prop-2-ynyl}-carbamic acid methyl ester), a small-molecule inhibitor with an IC50 of 23 nM against ACC2, resulted in a reduction of serum glucose and triglyceride levels. However, compound A-875400 (R) ({(R)-3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methyl-prop-2-ynyl}-carbamic acid methyl ester), an inactive enantiomer of A-908292 (S) with approximately 50-fold less activity against ACC2, also caused a similar reduction in glucose and triglycerides, suggesting that the glucose-lowering effects in ob/ob mice may be mediated by other metabolic pathways independent of ACC2 inhibition. To characterize the pharmacological activity of these experimental compounds at a transcriptional level, rats were orally dosed for 3 days with either A-908292 (S) or A-875400 (R), and gene expression analysis was performed. Gene expression analysis of livers showed that treatment with A-908292 (S) or A-875400 (R) resulted in gene expression profiles highly similar to known peroxisome proliferator-activated receptor (PPAR)-α activators. The results suggest that, in vivo, both A-908292 (S) and A-875400 (R) stimulated the PPAR-α-dependent signaling pathway. These results were further supported by both an in vitro genomic evaluation using rat hepatocytes and immunohistochemical evaluation using 70-kDa peroxisomal membrane protein. Overall, the gene expression analysis suggests a plausible mechanism for the similar pharmacological findings with active and inactive enantiomers of an ACC2 inhibitor.
Footnotes
-
J.F.W. and Y.Y. contributed equally to this work.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.107.126938.
-
ABBREVIATIONS: ACC, acetyl CoA carboxylase; A-908292, {(S)-3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methyl-prop-2-ynyl}-carbamic acid methyl ester; A-875400, {(R)-3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methyl-prop-2-ynyl}-carbamic acid methyl ester; PPAR, peroxisome proliferator-activated receptor; LC, liquid chromatography; MS, mass spectrometry; ANOVA, analysis of variance; IVT, In Vitro Technologies; HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase; PMP70, 70-kDa peroxisomal membrane protein; A-859610, {3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methyl-prop-2-ynyl}-carbamic acid methyl ester; GW7647, 2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid.
- Received June 8, 2007.
- Accepted November 15, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|