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- Barlind, Jonas G., et al.
(author)
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Identification and design of a novel series of MGAT2 inhibitors
- 2013
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In: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 23:9, s. 2721-2726
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Journal article (peer-reviewed)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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| 2. |
- Chien, Yin-Hsiu, et al.
(author)
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Mudd's disease (MAT I/III deficiency) : a survey of data for MAT1A homozygotes and compound heterozygotes
- 2015
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In: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 10
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Journal article (peer-reviewed)abstract
- Background: This paper summarizes the results of a group effort to bring together the worldwide available data on patients who are either homozygotes or compound heterozygotes for mutations in MAT1A. MAT1A encodes the subunit that forms two methionine adenosyltransferase isoenzymes, tetrameric MAT I and dimeric MAT III, that catalyze the conversion of methionine and ATP to S-adenosylmethionine (AdoMet). Subnormal MAT I/III activity leads to hypermethioninemia. Individuals, with hypermethioninemia due to one of the MAT1A mutations that in heterozygotes cause relatively mild and clinically benign hypermethioninemia are currently often being flagged in screening programs measuring methionine elevation to identify newborns with defective cystathionine beta-synthase activity. Homozygotes or compound heterozygotes for MAT1A mutations are less frequent. Some but not all, such individuals have manifested demyelination or other CNS abnormalities. Purpose of the study: The goals of the present effort have been to determine the frequency of such abnormalities, to find how best to predict whether they will occur, and to evaluate the outcomes of the variety of treatment regimens that have been used. Data have been gathered for 64 patients, of whom 32 have some evidence of CNS abnormalities (based mainly on MRI findings), and 32 do not have such evidence. Results and Discussion: The results show that mean plasma methionine concentrations provide the best indication of the group into which a given patient will fall: those with means of 800 mu M or higher usually have evidence of CNS abnormalities, whereas those with lower means usually do not. Data are reported for individual patients for MAT1A genotypes, plasma methionine, total homocysteine (tHcy), and AdoMet concentrations, liver function studies, results of 15 pregnancies, and the outcomes of dietary methionine restriction and/or AdoMet supplementation. Possible pathophysiological mechanisms that might contribute to CNS damage are discussed, and tentative suggestions are put forth as to optimal management.
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| 6. |
- Plowright, Alleyn T., et al.
(author)
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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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In: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 4:1, s. 151-158
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Journal article (peer-reviewed)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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| 7. |
- Scott, James S., et al.
(author)
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Circumventing seizure activity in a series of G protein coupled receptor 119 (GPR119) agonists
- 2014
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In: Journal of Medicinal Chemistry. - : American Chemical Society. - 0022-2623 .- 1520-4804. ; 57:21, s. 8984-8998
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Journal article (peer-reviewed)abstract
- Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.
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| 8. |
- Stridfeldt, Elin, et al.
(author)
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Synthesis, Characterization and Unusual Reactivity of Vinylbenziodoxolones-Novel Hypervalent Iodine Reagents
- 2016
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In: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 22:45, s. 16066-16070
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Journal article (peer-reviewed)abstract
- A novel type of hypervalent iodine(III) reagents, vinylbenziodoxolones (VBX), has been synthesized in a one-pot reaction from 2-iodobenzoic acid. VBX is bench stable, has been thoroughly characterized and the cyclic structure is supported by X-ray analysis. The reactivity of VBX was investigated in vinylation of nitrocyclohexane, and delivered vinylated products with opposite regioselectivity compared to acyclic vinyl(aryl) iodonium salts. The reagents could become a powerful tool in vinylation reactions under both metal-free and metal-catalyzed conditions.
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| 9. |
- Wahlström, Niklas, et al.
(author)
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Synthetic Applications of Cyanoacetylated Bisindoles : Synthesis of Novel Cycloheptadiindoles, Indolocarbazoles, and Related Aza Analogues.
- 2007
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In: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 72:15, s. 5886-5889
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Journal article (peer-reviewed)abstract
- (Chemical Equation Presented) Cyclization reactions involving cyanoacetylated bisindoles have been studied, providing access to various novel cyclohepta[2,1-b:3,4-b′]diindole derivatives as well as some related fused pentacyclic systems. Treatment of 3-cyanoacetyl-2,3′-diindolylmethane with methanesulfonic acid gave 6-(cyanomethyl)indolo[3,2-b]carbazole in a good yield.
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