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  • There is literature precedence for the metabolic activation


    There is literature precedence for the metabolic activation of the methylene carbons adjacent to the ring oxygen(s) of dioxanes and benzopyrans resulting in ring-opened electrophilic carbonyl species. Based on the potential for this metabolic pathway being operative with , a steric block approach was pursued in parallel to a metabolic pathway analysis of . From multiple options for such an approach, incorporation of a quaternary center at the side chain attachment juncture was selected for initial follow-up. Compound was found to be a relatively weak inhibitor of DGAT-1 in both microsomal enzyme preparations and the triglyceride synthesis whole cell assay. The high similarity between predicted conformations of and suggests that the methyl group is making an unfavorable interaction with the enzyme. Further extensions of this steric block approach were not pursued following the findings that is very stable in human liver microsomes () and there is no evidence for the formation of electrophilic species in this setting. The design goal of achieving improved passive permeability was realized in compound (7.7×10cm/s vs 1×10cm/s for ). As predicted, incorporation of the dioxinyl-based bicyclic core raised log nearly one order of magnitude relative to , driving the improved passive permeability. However, the overall polarity of log=0.74) is still in favorable property space as evidenced by the lack of turnover in human liver microsomes () and low clearance (2mL/min/kg) observed in rat. A clean profile (IC >10μM) against a broad panel of receptor, enzyme and channel targets is also consistent with the moderate lipophilicity of . This carboxylic BI-847325 receptor has low QTc potential (8% inhibition of hERG channel at 30μM) and was negative in Ames/in vitro micronucleus genetic toxicology screens. In a four-day rat toleration study (5, 50 and 500mg/kg), produced no treatment related changes in clinical signs, hematology or histopathology. As a measure of target inhibition in vivo, a triglyceride tolerance test in mice was carried out with . Since DGAT-1 is highly expressed in the small intestine and catalyzes the rate determining step in triglyceride synthesis, co-dosing of an inhibitor with an oral bolus of lipid provides a rapid confirmation of proof of mechanism. Doses of 1mg/kg (po) of were found to completely suppress plasma triglyceride excursion following a lipid challenge (). These results compare favorably with those seen for and in this model. In summary, the design goals of mimicking the conformational orientation of the pharmacophore elements of , while reducing hydrophilicity were achieved in a dioxinylpyrimidine-based chemotype. An efficient, homochiral synthetic route to this class of compounds was developed and utilized to confirm predictions regarding the relationship between structure and DGAT-1 inhibitory activity. The preclinical efficacy, pharmacokinetic and safety profiles described here are consistent with the profile we sought in a potential back-up to clinical lead . Acknowledgements
    Introduction Obesity is one of the leading metabolic diseases worldwide and is closely associated with diabetes, hypertension and cardiovascular disease [1]. There have been a great number of studies on the treatment of obesity, but more efficient therapeutic strategies need to be explored imminently. One of potential therapeutic methods involves inhibiting triacylglycerol (TG) synthesis. TG is a major form of energy storage in eukaryotic organisms. And the excess supply of TG in a tissue could lead to obesity [2]. A key enzyme in TG synthesis is acylcoenzyme A (CoA): diacylglycerol acyltransferase (DGAT), which catalyzes the final step of the TG synthesis pathway in mammalian cells by using diacylglycerol and fatty acyl CoA as substrates. Two isoforms of the DGAT enzyme are presently known namely, DGAT1 and DGAT2 [3], [4]. Although both enzymes utilize the same substrate, there is no homology between DGAT1 and DGAT2: DGAT1 belongs to the acyl-CoA: cholesterol acyltransferase (ACAT) gene family and DGAT2 is a member of a distinct and independent gene family. DGAT1 deficient mice are resistant to diet-induced obesity, have lower plasma glucose levels associated with an increase of insulin and leptin sensitivity and are also protected against diet-induced hepatic steatosis [5]. Previous studies reported that DGAT1 played a major role in modulating signals of energy homeostasis and a minor role in bulk TG synthesis [6]. Inhibition of DGAT1 might be an effective target for therapy of obesity and other related diseases. To date, several DGAT1 inhibitors (JTT-553, PF-04620110, AZD7687, LCQ908) have entered clinical trials in multiple pharmaceutical companies [7]. These DGAT1 inhibitors are widely available, but they have a great many limitations, including adverse effects and tolerability. Thus, efforts to discover novel, selective, orally bioavailable DGAT1 inhibitors have been intensified.