The enzymes involved in lipid biosynthesis pathways have att
The enzymes involved in lipid biosynthesis pathways have attracted considerable interest as potential targets for disruption of aberrant lipid accumulation and its resulting impact on a range of disease states.8, 9 Triglyceride biosynthesis and the resulting lipid burden placed on tissues are largely controlled by two major pathways in humans. The monoacylglyceride pathway is typically operative in tissues where dietary monoacylglycerides are reesterified, such as small intestine, liver and adipose. Fatty acids that enter this pathway come from dietary VKGILS-NH2 or via de novo fatty acid synthesis from acetyl CoA, via a series of enzyme-catalyzed homologation reactions. The second pathway, found in most cell types, is the glycerol phosphate pathway which sequentially adds two fatty acyl chains to glycerol-3-phosphate generating a phosphatidic acid intermediate that is subsequently converted to triglycerides. Both of these pathways converge at intermediate diacylglycerols which are then converted to triglycerides through acylation by a fatty acid acyl-CoA, catalyzed by acyl-CoA:diacylglycerol acyltransferases (DGAT). This family of enzymes is composed of DGAT-1 and DGAT-2, which while they carry out the same biotransformation, arise from divergent gene families.12, 13, 14 Consistent with the lipotoxicity hypothesis, mice lacking DGAT-1 (DGAT-1−/−) are resistant to diet-induced obesity and have increased insulin sensitivity and energy expenditure.15, 16 In addition, transplantation of white adipose tissue from these mice into the wild-type strain confers the enhanced metabolic profile observed in the DGAT-1 knockout mice. These studies have spurred research efforts to determine whether selective, small molecule inhibitors of DGAT-1 can produce the same improved metabolic profile observed in the DGAT-1−/− animals. Several research groups have disclosed potent and selective DGAT-1 inhibitors from several chemically-distinct series. Pre-clinical studies with these compounds have confirmed that small molecule DGAT-1 inhibitors can elicit metabolic outcomes comparable to those observed in DGAT-1−/− mice.19, 20, 21 We have recently disclosed an orally-active, novel DGAT-1 inhibitor PF-04620110 (1) which was advanced to human clinical trials for the treatment of type 2 diabetes. This pyrimidooxazepinone-based series arose from specific design criteria aimed at eliminating the potential photochemical and reactive metabolite risks associated with the pyrimidinooxazine-based DGAT-1 inhibitor 2. As compound 1 advanced into human clinical studies there were questions as to whether the poor passive permeability associated with agent would result in limited distribution into key in vivo compartments, potentially leading to a reduced efficacy maximum. This report details the discovery of neutral, potent and orally-active DGAT-1 inhibitors with high passive permeabilities and their resulting efficacy in preclinical rodent models. Analysis of the key pharmacophore elements of 1 will also be discussed as part of a broader structure–activity-relationship (SAR) analysis.