| 1. |
- Barlind, Jonas G, et al.
(författare)
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Design and optimization of pyrazinecarboxamide-based inhibitors of diacylglycerol acyltransferase 1 (DGAT1) leading to a clinical candidate dimethylpyrazinecarboxamide phenylcyclohexylacetic acid (AZD7687)
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:23, s. 10610-10629
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Tidskriftsartikel (refereegranskat)abstract
- A new series of pyrazinecarboxamide DGAT1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and physical and DMPK properties combined with a low predicted dose in man. Rational design and optimization of this series led to the discovery of compound 30 (AZD7687), which met the project objectives for potency, selectivity, in particular over ACAT1, solubility, and preclinical PK profiles. This compound showed the anticipated excellent pharmacokinetic properties in human volunteers.
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| 2. |
- Barlind, Jonas G., et al.
(författare)
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Identification and design of a novel series of MGAT2 inhibitors
- 2013
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 23:9, s. 2721-2726
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Tidskriftsartikel (refereegranskat)abstract
- [Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to naive, p < 0.01) in plasma triacylglycerol (TAG) concentration.
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| 3. |
- Plowright, Alleyn T., et al.
(författare)
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Design and synthesis of a novel series of cyclohexyloxy-pyridyl derivatives as inhibitors of diacylglycerol acyl transferase 1
- 2013
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 4:1, s. 151-158
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Tidskriftsartikel (refereegranskat)abstract
- A novel series of potent diacylglycerol acyl transferase 1 inhibitors was developed from the clinical candidate AZD3988. Replacement of the phenyl cyclohexyl-ethanoate side chain with substituted oxy-linked side chains to introduce changes in shape and polarity, reduce lipophilicity and mask the hydrogen bond donors with internal hydrogen bond acceptors led to improvements in solubility, unbound clearance and excellent selectivity over the related enzyme acyl-coenzyme A:cholesterol acyltransferase 1. A comparison of the small molecule crystal structures of compound 4 and compound 28 is described. Compounds in this series have good ADMET properties and provide an exposure-dependent decrease in circulating plasma triglyceride levels in a rat oral lipid tolerance test.
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| 4. |
- Swales, John G., et al.
(författare)
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Quantitation of Endogenous Metabolites in Mouse Tumors Using Mass-Spectrometry Imaging
- 2018
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Ingår i: Analytical Chemistry. - : AMER CHEMICAL SOC. - 0003-2700 .- 1520-6882. ; 90:10, s. 6051-6058
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Tidskriftsartikel (refereegranskat)abstract
- Described is a quantitative-mass-spectrometry-imaging (qMSI) methodology for the analysis of lactate and glutamate distributions in order to delineate heterogeneity among mouse tumor models used to support drug-discovery efficacy testing. We evaluate and report on preanalysis-stabilization methods aimed at improving the reproducibility and efficiency of quantitative assessments of endogenous molecules in tissues. Stability experiments demonstrate that optimum stabilization protocols consist of frozen-tissue embedding, post-tissue-sectioning desiccation, and storage at -80 degrees C of tissue sections sealed in vacuum-tight containers. Optimized stabilization protocols are used in combination with qMSI methodology for the absolute quantitation of lactate and glutamate in tumors, incorporating the use of two different stable-isotope-labeled versions of each analyte and spectral-clustering performed on each tissue section using k-means clustering to allow region-specific, pixel-by-pixel quantitation. Region-specific qMSI was used to screen different tumor models and identify a phenotype that has low lactate heterogeneity, which will enable accurate measurements of lactate modulation in future drug-discovery studies. We conclude that using optimized qMSI protocols, it is possible to quantify endogenous metabolites within tumors, and region-specific quantitation can provide valuable insight into tissue heterogeneity and the tumor microenvironment.
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