94944-70-4

Usage

Uses

Used in Immunosuppressive Applications:
1-[4-(1,2,3,4-TETRAHYDROXYBUTYL)-1H-IMIDAZOL-2-YL]ETHANONE is used as an immunosuppressive agent for the treatment of autoimmune disorders. By inhibiting S1P lyase, it increases lymphoid tissue S1P concentrations, reducing lymphocyte egress from thymus and peripheral lymphoid organs. This results in reversible lymphopenia and therapeutic levels of immunosuppression without causing non-lymphoid lesions associated with synthetic S1P receptor agonists.
Used in Pharmaceutical Industry:
In the pharmaceutical industry, 1-[4-(1,2,3,4-TETRAHYDROXYBUTYL)-1H-IMIDAZOL-2-YL]ETHANONE is used as a potential drug candidate for the development of new immunosuppressants. Its unique mechanism of action and ability to modulate immune responses make it a promising option for treating various autoimmune and inflammatory conditions.

Biochem/physiol Actions

2-Acetyl-5-tetrahydroxybutyl imidazole (THI) can block S1P lyase in vivo and up-regulates circulatory and tissue S1P levels. It has the ability to repress dystrophic muscle degeneration.

References

1) MacKenzie et al. (1992), Toxicity Studies of Caramel Colour III and 2-Acetyl-4(5)-Tetrahydroxybutylimidazole in F344 rats; Food Chem. Toxicol. 30 417 2) Ohtoyo et al. (2015), Sphingosine 1-phosphate lyase inhibition by 2-acetyl-4-(tetrahydroxybutyl)imidazole (THI) under conditions of vitamin B6 deficiency; Mol.Cell Biochem. 400 125 3) Gugasyan et al. (1998), Emigration of mature T cells from the thymus is inhibited by the imidazole-based compound 2-acetyl-4-tetrahydroxybutylimidazole; Immunology 93 398 4) Schwab et al. (2005), Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients; Science 309 1735 5) Bradbury et al. (1997), The immunomodulatory compound 2-acetyl-4-tetrahydroxybutyl imidazole causes sequestration of lymphocytes in non-lymphoid tissue; Immunol. Cell Biol. 75 497

InChI:InChI=1/C9H14N2O5/c1-4(13)9-10-2-5(11-9)7(15)8(16)6(14)3-12/h2,6-8,12,14-16H,3H2,1H3,(H,10,11)/t6-,7-,8-/m1/s1

Upstream product

• 67-56-1 methanol 
• 19479-65-3 2-ethoxyacrylonitrile 
• 4710-95-6 D-(+)-glucosamine hydrochloride 
• 1201794-87-7 1-amino-1-deoxy-D-fructose acetic acid salt 
• 26419-66-9 2-methyl-1,3-dithiolane-2-carboxaldehyde 
• 643-71-0 D-glucosone 
• 1294498-22-8 C₆H₁₁NO₂ 
• 6333-49-9 1-amino-1-deoxy-D-arabino-hexulose acetate 
• 66-84-2 D-(+)-glucosamine hydrochloride 
• 1078691-95-8 (+)-D-glucosamine hydrochloride 
• 185798-10-1 1-[4-((S)-2,2-Diethyl-[1,3]dioxolan-4-ylethynyl)-1-ethoxymethyl-1H-imidazol-2-yl]-ethanone 
• 185798-08-7 4-((S)-2,2-Diethyl-[1,3]dioxolan-4-ylethynyl)-1-ethoxymethyl-1H-imidazole 
• 185798-25-8 (1'R,2'S,3'R)-2-acetyl-4-<3',4'-O-(3'-pentylidene)-1',2',3',4'-tetrahydroxy-1'-butyl>-1-(ethoxymethyl)imidazole 
• 170882-83-4 (3'S)-(E)-2-acetyl-4-<3',4'-O-(3'-pentylidene)-3',4'-dihydroxybut-1'-enyl>-1-(ethoxymethyl)imidazole 

Downstream Products

• 1160957-37-8 (1R,2S,3R)-1-(2-(1-hydroxyethyl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol 
• 1160957-32-3 1-(1-methyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone 
• 948840-55-9 1-(5-((4S,4'R,5R)-2,2,2',2'-tetramethyl-4,4'-bi(1,3-dioxolan)-5-yl)-1H-imidazol-2-yl)ethanone 
• 1258455-15-0 C₉H₆⁽²⁾H₈N₂O₅ 
• 1258455-14-9 C₁₈H₂₆N₄O₉ 

Relevant academic research and scientific papers

Asymmetric synthesis of (1R,2S,3R)-2-acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole

A method for preparing the biologically active compound (1R,2S,3R)-2-acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole 1 using a palladium (0) catalysed coupling of 1-ethoxymethyl-4-iodomidazole 2 to the functionalised vinylstannane 3 and the Sharpless catalytic asymmetric dihydroxylation is reported.

Asymmetric synthesis of 2-acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazoles

A method for preparing the eight stereoisomers of the biologically active compound (1R,2S,3R)-2-acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole (THI, 1) is reported. This method employs a palladium(0)-catalyzed coupling of 1-(ethoxymethyl)-4-iodoimidazole (7) to functionalized vinylstannanes (R)- or (S)-12a,b or 13a,b or 1-alkynylstannanes (R)- or (S)-6a,b to introduce the C-4 imidazole four-carbon side chain. The 1,2-dihydroxy functionality of the butyl side chain was introduced by Sharpless catalytic asymmetric dihydroxylation reactions.

COMPOUNDS AND USE THEREOF FOR THE TREATMENT OF INFECTIOUS DISEASES AND CANCER

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.

Practical synthesis of potent sphingosine-1-phosphate lyase inhibitors THI and LX2931

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).

METHODS OF PREPARING 1-(4-((1R,2S,3R)-1,2,3,4-TETRAHYDROXYBUTYL)-1H-IMIDAZOL-2-YL)ETHANONE

Methods of preparing 1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone and derivatives thereof are disclosed.

Inhibition of sphingosine-1-phosphate lyase for the treatment of autoimmune disorders

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.

Methods of Preparing Imidazole-Based Compounds

Methods of preparing imidazole-based compounds are disclosed. Particular compounds are of formula I: