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Methods and compositions for diagnostic and therapeutic targeting of cox-2

A technology of COX-2 and diagnostic agents, applied in the field of derivatives of non-steroidal anti-inflammatory drugs

Inactive Publication Date: 2009-09-09
VANDERBILT UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Furthermore, in the case of cancer, the lack of targeting ligands capable of binding multiple tumor types necessitates the synthesis of many active agents for the treatment and / or diagnosis of different tumor types

Method used

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  • Methods and compositions for diagnostic and therapeutic targeting of cox-2
  • Methods and compositions for diagnostic and therapeutic targeting of cox-2
  • Methods and compositions for diagnostic and therapeutic targeting of cox-2

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0453] Synthesis of representative therapeutic analogs

[0454] Compound 27j: Indo-sulfathiazole analog :pass figure 1 Compound 27j was synthesized by the method described in . Briefly, compound 27j was synthesized by first complexing succinic anhydride and sulfathiazole in tetrahydrofuran (THF) at room temperature in the presence of triethylamine (TEA) for 6 hours to prepare a white solid. succinylsulfathiazole (67% yield). Subsequently, at room temperature and in the presence of TEA, succinylsulfathiazole was mixed with O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU) in dichloromethane 2 hours to prepare the corresponding succinimide ester, then at room temperature and in the presence of TEA, the succinimide ester and 1-(4-aminobutyl)-2-{1-(4-chlorobenzene Formyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide was reacted in dichloromethane for 16 hours to prepare compound 27j as a yellow gum (45% yield). Compound 27j was characterized by NMR, two...

Embodiment 2

[0482] Synthesis of Representative Diagnostic Analogs

[0483] Compound 27z: Fluorescent Indo-dansyl analog :pass Figure 4 Compound 27z was synthesized by the method described in . Briefly, at room temperature and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), dimethyl Complexation of indomethacin with N-BOC butanediamine in the presence of diaminopyridine (DMAP), N,N'-diisopropylethylamine (DIPEA) and N,N-dimethylformamide (DMF) 16 hours. A yellow solid was obtained corresponding to a percent yield of 72%. This solid was then dissolved in dichloromethane and treated with HCl(g) at room temperature for 2 hours to produce N-(4-aminobutyl)-2-[1-(4-chlorobenzyl) as a brown solid Acyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide hydrochloride (98% yield), N-(4 -Aminobutyl)-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide hydrochloride and triethylamine ( TEA) was reacted in dichloromethane for 5 minute...

Embodiment 3

[0530] Determination of IC using purified enzyme 50

[0531] Cyclooxygenase activity of sheep COX-1 (44 nM) or human COX-2 (130 nM) was analyzed by TLC. A 200 μL reaction mixture was composed of hematin-reconstituted protein in 100 mM Tris-HCl (pH 8.0), 500 μM phenol and [1- 14 C]-arachidonic acid (50 μM, about 55-57 mCi / mmol; PerkinElmer Life And Analytical Sciences, Inc., Wellesley, Massachusetts, United States of America). For the analysis of inhibition over time, the heme-reconstituted protein was preincubated for 17 minutes at room temperature, and then preincubated in DMSO for 3 minutes at 37°C using various concentrations of the composition of the present disclosure, followed by Add [1- 14 C]-Arachidonic acid (50 [mu]M) for 30 sec. in Et 2 O / CH 3 The reaction was terminated by solvent extraction in OH / 1M citrate (pH 4.0, 30:4:1). The phases were separated by centrifugation at 2000 g for 5 minutes and the organic phase was spotted onto 20x20 cm TLC plates (Liese...

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Abstract

The present invention discloses compositions that selectively bind cyclooxygenase-2 and comprise a therapeutic and / or diagnostic moiety. Also provided are methods for using the disclosed compositions for diagnosing (i.e., by imaging) a target cell and / or treating a disorder associated with a cyclooxygenase-2 biological activity.

Description

[0001] Cross References to Related Applications [0002] The subject matter of the present disclosure claims priority to US Provisional Patent Application Serial No. 60 / 814,854, filed June 19, 2006, the disclosure of which is incorporated by reference in its entirety into this disclosure. [0003] funding statement [0004] This work was supported by grant U54-CA 105296 from the United States National Institutes of Health. Accordingly, the United States Government has rights in the subject matter of this disclosure. technical field [0005] The subject matter of the present disclosure relates generally to diagnostic and therapeutic agents comprising COX-2 selective ligands. More specifically, the subject-matter of the present disclosure relates to derivatives of non-steroidal anti-inflammatory drugs which exhibit selective binding to cyclooxygenase-2 (COX-2) and contain such that they can be used as diagnostic and / or The functional group of the therapeutic agent. Backg...

Claims

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Application Information

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IPC IPC(8): A61K31/404A61K31/5355
CPCA61K49/0041A61K49/0017A61K31/5383A61K49/0032A61K49/0052A61K31/655A61K49/0028A61K31/416A61K49/003A61K49/0021A61K31/405A61K47/481A61K31/4745A61K47/55A61P29/00A61P35/00
Inventor L·J·马尼特MD.·J·乌丁B·C·克鲁斯
Owner VANDERBILT UNIV
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