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Carboxylic acids and derivatives thereof and pharmaceutical compositions containing them

A composition and drug technology, applied in the direction of drug combination, anhydride/acid/halide active ingredients, medical preparations containing active ingredients, etc.

Inactive Publication Date: 2008-02-27
SYNDROMEX LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no ligand has been identified for HNF-4α that could serve as a basis for designing inhibitors of HNF-4α transcriptional activity

Method used

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  • Carboxylic acids and derivatives thereof and pharmaceutical compositions containing them
  • Carboxylic acids and derivatives thereof and pharmaceutical compositions containing them
  • Carboxylic acids and derivatives thereof and pharmaceutical compositions containing them

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Long-chain acyl-CoAs are ligands for HNF-4α

[0101] Acyl-CoAs of various chain lengths and degrees of saturation were found to bind specifically to HNF-4α.

[0102] Binds to the HNF-4α ligand-binding domain incorporated into glutathione-S-transferase (GST-HNF-4α (LBD)) or to the full-length HNF-4α protein tagged with 6 histidines (His-HNF-4α )as an example. Palmitoyl(16:0)-CoA bound to the ligand-binding domain or full-length HNF-4α protein is saturable with a Kd of 2.6 μM and approaches the saturation of 1 mole of fatty acyl-CoA / mole of HNF-4α ( Figure 1A). Binding is specific for acyl-CoA and has no activity against free fatty acids or free CoA. Binding of acyl-CoAs of various chain lengths and degrees of saturation was demonstrated by competition with radiolabeled palmitoyl(16:0)-CoA bound to recombinant GST-HNF-4α (LBD) or His-HNF-4α (attached Figure 1B). No binding was observed for saturated fatty acyl-CoAs with chain lengths shorter than C12. However, the b...

Embodiment 2

[0105] Regulation of HNF-4α activity by long-chain acyl-CoAs

[0106]HNF-4α activity as a function of long-chain acyl-CoA binding by studying the association of HNF-4α with its apo CIII promoter sequence (-87 / -66)6 C3P elements at various chain lengths with or without addition, saturation, Binding in the presence of acyl-CoA and degree of substitution were evaluated.

[0107] Binding was confirmed by gel mobility shift analysis. As shown in Figure 2, as the concentration of His-HNF-4α increases, the binding of C3P to HNF-4α also increases and is activated by natural saturated fatty acyl-CoA with a chain length of C12-C16. Activation was concentration dependent and was maximal in the presence of myristoyl(14:0)-CoA in the concentration range required for its binding to HNF-4α. Furthermore, some fatty acyl-CoAs as well as heterologous acyl-CoAs were found to act as true HNF-4α antagonists, ie inhibit their internal binding to their cognate enhancers.

[0108] Thus, incubation...

Embodiment 3

[0110] Regulation of HNF-4α-induced transcription by HNF-4α agonists and antagonists

[0111] The effects of agonistic or antagonistic HNF-4α-ligands were further analyzed by analysis catalyzed by addition of HeLa nuclear extracts, induced by recombinant HNF-4α, initiated by HSV thymidine kinase and chicken ovalbumin promoter, and induced by apo The in vitro transcription rate of the test template consisting of a 377 bp G-less cassette enhanced by three copies of the CIII gene promoter was evaluated. Transcriptional activation by HNF-4α was assessed in the presence or absence of added representative long-chain fatty acyl-CoAs. Template transcription consisting of a 200 bp G-less cassette driven by the adenoviral major late major (AdML) promoter and lacking the HNF-4α enhancer was used as an internal control template. As shown in Figure 3, the in vitro transcription of the test template increased as a function of HNF-4α, and was close to saturation when the concentration of HN...

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Abstract

In accordance with the present invention, there are provided therapeutically effective compounds comprising an amphipathic carboxylate of the formula R-COOH, or a salt or an ester or amide of such compound, where R designates a saturated or unsaturated alkyl chain of 10-24 carbon atoms, one or more of which may be replaced by heteroatoms, where one or more of said carbon or heteroatom chain members optionally forms part of a ring, and where said chain is optionally substituted by a hydrocarbyl radical, heterocyclyl radical, lower alkoxy, hydroxyl-substituted lower alkyl, hydroxyl, carboxyl, halogen, phenyl or (hydroxy-, lower alkyl-, lower alkoxy-, lower alkenyl- or lower alkinyl)-substituted phenyl, C3-C7 cycloalkyl or (hydroxy-, lower alkyl-, lower alkoxy-, lower alkenyl- or lower alkinyl)-substituted C3-C7 cycloalkyl wherein said amphipathic carboxylate is capable of being endogenously converted to its respective coenzyme A thioester.

Description

[0001] This application is a divisional application of No. 98806550.9 patent application for invention filed on June 23, 1998, entitled "Carboxylic Acids and Their Derivatives and Pharmaceutical Compositions Containing Them". [0002] The technical field of the present invention [0003] The present invention relates to therapeutically useful compounds and methods of using such compounds to treat certain diseases / syndromes. [0004] references [0005] The following references are incorporated into this application by numbers in parentheses or superscripts at the relevant parts of the application. [0006] 1. Sladek, F.M., Zhong, W.M., Lai, E. Darnell, J.E., Jr. Gene Dev. 4, 2353-2365 (1990) [0007] 2. Sladek, F.M., in Liver Gene Expression (eds. Tronche, F. & Yaniv, M.) pp.207-230, R.G. Landes Co., Austin, TX (1994) [0008] 3. The Metabolic and Inherited Bases of Inherited Disease (eds., Scriver, C.R., Beaudet, A.L., Sly, W.S., Valle, D.) Vol.II Part8, 1995 (McGraw-Hill, I...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/19A61K31/20A61P3/00A61P9/12A61P9/10A61P35/00A61P3/06A61K31/00A61K31/16A61K31/192A61K31/201A61K31/202A61K31/23A61K31/231A61K31/232A61K31/69A61P3/10A61P7/02A61P17/06A61P19/02A61P25/00A61P29/00A61P43/00
CPCA61K31/69Y10S514/825A61K31/7076Y10S514/824A61K31/202Y10S514/903A61K31/20A61K31/00A61K31/201A61K31/192A61P17/06A61P19/02A61P25/00A61P29/00A61P3/00A61P35/00A61P3/06A61P43/00A61P7/02A61P9/10A61P9/12A61P3/10
Inventor 詹考伯·巴-塔那
Owner SYNDROMEX LTD