December 31, 2012
These acetyl-CoA carboxylase inhibitors may help obese patients. D. A. Griffith and co-inventors prepared pyrazolospiroketone derivatives represented by structures 1 and 2 (Figure 1) that inhibit acetyl coenzyme A (acetyl-CoA) carboxylases (ACCs). These inhibitors have the potential to treat obesity and related conditions.
ACCs regulate the biosynthesis and metabolism of fatty acids. They catalyze the carboxylation of acetyl-CoA to form malonyl-CoA, a building block for the biosynthesis of fatty acids. ACC1 and ACC2 are the two main isoforms of ACC in mammals. ACC1 is expressed at high levels in lipogenic tissues and regulates long-chain fatty acid biosynthesis. ACC2 is the predominant isoform in heart and skeletal muscle; it regulates β-oxidation of fatty acids by inhibiting carnitine palmitoyl transferase.
Hepatic lipid accumulation causes hepatic insulin resistance and contributes to the pathogenesis of type 2 diabetes. In vivo studies also showed that the two ACC isoforms must be reduced to significantly reduce lipid accumulation and improve insulin action. Inhibiting ACC enzymes is thus a viable therapeutic target for treating obesity because it increases fatty acid oxidation and suppresses fatty acid synthesis, a combination that may lead to loss of body fat in obese patients.
The molecules introduced by the inventors inhibit ACC1, ACC2, or both. They may provide a treatment for obesity and obesity-related diseases such as nonalcoholic fatty liver disease and type 2 diabetes.
The inventors describe the synthesis of 73 examples, four of which (3–6) are shown in Figure 2. In addition to the general structure claims, they claim 21 structures specifically by chemical name or structure.
The inventors used preparations of recombinant human ACC1 (rhACC1) and recombinant human ACC2 (rhACC2) to determine the direct inhibition of ACC activity by compounds with structures 1 and 2. IC50 values were reported for 49 compounds; the table contains results for the four representative examples.
|Compound||rhACC1 IC50, nM||rhACC2 IC50, nM|
(Pfizer [New York]. WIPO Publication 2012143813, Oct. 26, 2012; Ahmed F. Abdel-Magid)
This patent was originally reviewed in ACS Medicinal Chemistry Letters.
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