Journal
CHEMICAL & PHARMACEUTICAL BULLETIN
Volume 58, Issue 5, Pages 673-679Publisher
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/cpb.58.673
Keywords
acyl coenzyme A: diacylglycerol acyltransferase-1 inhibitor; obesity; KKA(y)
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In a program to discover new small molecule diacylglycerol acyltransferase (DGAT)-1 inhibitors, screening of our in-house chemical library was carried out using recombinant human DGAT-1 enzyme. From this library, the lead compound la was identified as a new class of DGAT-1 inhibitor. A series of novel N-(substituted heteroary1)-4-(substituted phenyl)-4-oxobutanamides 2 was designed from la, synthesized and evaluated for inhibitory activity against DGAT-1 enzyme. Among these compounds, N-(5-benzyl-4-phenyl-1,3-thiazol-2-yl)-4-(4,5-diethoxy-2-methylpheny1)-4-oxobutanamide 9 was found to exhibit potent inhibitory activity and good enzyme selectivities. Following administration in KKA(y) mice with 3 mg/kg high fat diet admixture for four weeks, 9 reduced body weight gain and white adipose tissue weight without affecting total food intake. These results suggested that the small molecule DGAT-1 inhibitor might have potential in the treatment of obesity and metabolic syndrome.
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