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  • For the SAR optimization of


    For the SAR optimization of the right hand side, it was decided to explore the inclusion of the key carboxylic BMS-354825 moiety present in the original DGAT-1 inhibitors from . Analogs were constructed by the synthetic routes outlined in , . In , the methylene-oxy linker was introduced by condensation of 2-chloro-5-nitro-pyridine with 4-hydroxymethyl-piperidine. Activation of alcohol as the mesylate and subsequent coupling with methyl 3-hydroxybenzoate provided intermediate . Standard hydrogenation of the nitro group, HATU promoted amide formation, and hydrolysis of the ester produced target and similar analogs. The reverse oxy-methylene linker was assembled by addition of 4-hydroxy-piperidine to 2-chloro-5-nitro-pyridine (). Subsequent alkylation with methyl 3-(bromomethyl)benzoate yielded intermediate which was converted to target by the usual steps. Selected biological data are collated in . Compounds which were active in the in vitro assay (IC <100nM) were subsequently tested in the in vivo mouse postprandial triglyceride (PPTG) assay. Our first discovery was that introduction of the carboxylic acid in the urea analog exhibited an increase in biological activity and a significant increase in blood levels. Replacement of the urea linker by a methylene ether linker (analogs –) indicated a preference for the carboxylic acid at the position in . The reverse oxy-methylene linker in displayed slightly lower biological activity. Substituting the piperidine ring with a pyrrolidine ring in analogs – or inserting a methylene linker to the carboxylic acid in did not improve inhibition of the DGAT-1 enzyme. The central pyridine ring appeared to be important for biological activity (). Substitution by a pyrimidine ring or phenyl ring – resulted in a decrease in DGAT-1 inhibition. These analogs were synthesized by the route depicted in using 2-chloro-5-nitropyrimidine, 1-fluoro-4-nitrobenzene, or 1,2-difluoro-4-nitrobenzene as starting reagents. With the identified 2-pyridinyl-4-piperidinyl-methoxybenzoic acid right hand side, reoptimization of the left hand side was surveyed, and key analogs are presented in . Compound demonstrated selectivity over hDGAT-2 (IC=1.3μM), hACAT-2 (IC=4.7μM), and hACAT-1 (IC=0.8μM) and revealed no hERG, PXR, or liver enzyme (2D6, 3A4, and 2C9) inhibition issues. Substitution of the 5-phenyl-benzofuran with the 5-phenyl-thiophene showed a slight decrease of in vivo activity. Conversion of the 5-phenyl-benzofuran to the 5-oxazole-benzofuran or 5-thiazole-benzofuran produced a decrease in DGAT-1 activity. Compound which incorporated our original piperidinyl-oxazole left hand side was not superior to the 5-phenyl-benzofuran moiety. Replacement of the 5-phenyl-benzofuran with the napthalene analog or quinoline analog also resulted in a decrease in biological activity. While the biphenyl ether compounds – both exhibited good in vitro DGAT-1 inhibition and similar rat pharmacokinetic profiles, the substituted analog showed better in vivo activity in the mouse PPTG assay. Target compound was selective over hDGAT-2 (IC >50μM), hACAT-2 (IC >40μM), and hACAT-1 (IC=3μM), presented no hERG or PXR issues, but did slightly inhibit liver enzymes 3A4 and 2C9 (IC=5μM). In comparison to the ether compounds –, the keto analog and extended ether analog demonstrated reduced activity. The alkylphenyl ether displayed lower in vivo activity while retaining reasonable blood levels. In conclusion, novel DGAT-1 inhibitors based on a pyridine-carboxamide core have been discovered. Systematic SAR investigation has optimized the original lead compound into compounds and . Both compounds and exhibit selectivity for hDGAT-1, lower triglyceride levels at a 3mg/kg dose in our in vivo mouse PPTG assay, and exhibit minimal off-target issues. Additional SAR results will be the subject of future publications.
    Introduction It is estimated that the global primary energy demand will nearly double from 1990 (12 TW/348 quadrillion Btu) to 2030 (23 TW/687 Btu) (EIA, 2010). Reasons for the increased demand are a growing world population (7 billion today to 9.3 billion in 2050) (DSW, 2010) and increasing living standards, especially in industrially fast growing countries like India and China. On the other hand, easily accessible natural fossil fuel reserves will decline and production cost are expected to increase correspondingly (Stephens et al., 2010). The combustion of fossil fuels causes environmental problems which are foreseen to escalate if no action is taken to prevent the release of greenhouse gases (IPCC, 2007). New and environmentally friendly energy sources will increasingly become important in the future. Substantial research effort has been put into the development of alternative energy supply to use the natural energy sources, i.e. wind, water, geothermal and solar. The solar light energy which reaches the earth's surface is abundant and corresponds to ca. 5600 times the global energy demand of 2005 (Schenk et al., 2008). However, due to the fact that light energy is dispersed, utilization of solar energy is difficult. Photosynthetic organisms like plants and algae have evolved the ability to harvest solar energy and convert it into chemical molecules (biomass). BMS-354825 Research over the last years has focused on the utilization of plant biomass to produce bioethanol, biodiesel, biomethane or BTL fuels (Schenk et al., 2008). Energy plants are used as renewable substrates for these processes, which have to be grown on arable land. Since this high-value land area is limited (ca. 3.5% of the earth's surface) (CIA, 2007), growth of energy plants is in direct competition with plant growth for food and feed production, with obvious ethical implications. Microalgae offer a number of potential advantages compared to higher plants. The cells can be cultivated on non-arable, low value land and high biomass yields are possible (Carlsson et al., 2007). Furthermore, the lipid content of some species (the basis for biodiesel production), can be extremely high, reaching over 60% of their dry biomass (DW) (Metzger and Largeau, 2005). Today the use of microalgae for biofuel production is limited because of the high production cost which makes it necessary that methods have to be developed to increase the production of valuable, high energy biomass.