- Practical synthesis of potent sphingosine-1-phosphate lyase inhibitors THI and LX2931
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A practical and scalable synthesis of in vivo sphingosine-1-phosphate lyase inhibitor LX2931 (1) is described. The synthetic route features an improved Büchi cyclocondensation of 2-ethoxyacrylonitrile (3) with either 1-amino-1-deoxy-d-fructose acetate (4a) or d-(+)-glucosamine hydrochloride (4b) to produce 1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone (2, THI), followed by oximation of THI and acid-promoted oxime isomerization to give LX2931 (1).
- Zhang, Haiming,Yan, Jie,Bednarz, Mark S.,Hernandez, Gonzalo,Lu, Yuelie,Courtney, Lawrence F.,Chen, Jason,Hu, Weifeng,Liu, Renmao,Yang, Xiaogen,Wu, Wenxue
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- Inhibition of sphingosine-1-phosphate lyase for the treatment of autoimmune disorders
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During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.
- Bagdanoff, Jeffrey T.,Donoviel, Michael S.,Nouraldeen, Amr,Tarver, James,Fu, Qinghong,Carlsen, Marianne,Jessop, Theodore C.,Zhang, Haiming,Hazelwood, Jill,Nguyen, Huy,Baugh, Simon D. P.,Gardyan, Michael,Terranova, Kristen M.,Barbosa, Joseph,Yan, Jack,Bednarz, Mark,Layek, Suman,Courtney, Lawrence F.,Taylor, Jerry,Digeorge-Foushee, Ann Marie,Gopinathan, Suma,Bruce, Debra,Smith, Traci,Moran, Liam,O'Neill, Emily,Kramer, Jeff,Lai, Zhong,Kimball, S. David,Liu, Qingyun,Sun, Weimei,Yu, Sean,Swaffield, Jonathan,Wilson, Alan,Main, Alan,Carson, Kenneth G.,Oravecz, Tamas,Augeri, David J.
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- COMPOUNDS AND USE THEREOF FOR THE TREATMENT OF INFECTIOUS DISEASES AND CANCER
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The invention provides the imidazole, oxazole and thiazole compounds and use thereof in methods for treating a disease or a disorder, such as infectious diseases and cancer, wherein inhibition of sphingosine-1-phosphate lyase is beneficial to treat the disease or the disorder.
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Page/Page column 35; 39
(2021/02/26)
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- Methods of Preparing Imidazole-Based Compounds
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Methods of preparing imidazole-based compounds are disclosed. Particular compounds are of formula I:
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Page/Page column 5-6
(2008/12/04)
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