Patent Watch

September 23, 2013

Fight obesity and metabolic disorders with DGAT1 inhibitors. R. J. Devita and co-inventors disclose imidazole derivatives represented by formula 1. The compounds are diacylglycerol O-acyltransferase 1 (DGAT1) inhibitors that may be useful for treating obesity, hyperlipidemia, and diabetes mellitus.

A major cause of obesity is the accumulation of triglycerides in adipose tissue. Dietary triglycerides are hydrolyzed by pancreatic lipase to 2-monoacylglycerol and fatty acids, which are absorbed by intestinal epithelial enterocytes. The absorbed hydrolysis products are used to resynthesize triglycerides through the monoacylglycerol pathway in the small intestine.

This pathway includes two sequential acylation steps: The first is catalyzed by monoacylglycerol O-acyltransferases and the second by DGATs. Another route is the glycerol 3-phosphate pathway that is present in most tissues.

DGATs that catalyze the final step of triglyceride synthesis contain two subtypes, DGAT1 and DGAT2. These isozymes catalyze similar reactions, but are not homologous to each other.

DGAT1 is present in the small intestine, adipose tissue, and liver. It is believed to play a role in lipid absorption and accumulation in the fat cells and in the liver. Studies on genetically modified mice and pharmacological data suggest that DGAT1 inhibition is a promising target for treating obesity and type 2 diabetes. Thus, DGAT1 inhibitors such as the compounds disclosed by the inventors may provide effective treatments for obesity and other metabolic disorders.

General formula and four examples of DGAT1 inhibitors

The inventors report synthesis procedures for and structures of 182 examples of the compounds of formula 1, including 24 shown in the figure. They evaluated the compounds by using the human DGAT1 (hDGAT1) CPM assay. CPM is 7-diethylamino-3-(4-maleimidophenyl)-4-methylcoumarin; it reacts with sulfhydryl groups to form an easily detected fluorescent product.

The inventors report IC50 values for the 182 examples. The values for examples 24 are shown in the table. Unfortunately, the IC50 concentration units are not specified.

Example hDGAT1
2 5.833
3 4.838
4 1.902

(Merck Sharp & Dohme [Rahway, NJ]. WIPO Publication 2013096093, June 27, 2013; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.


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