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Hiv Prodrugs Cleavable by Cd26

a technology of prodrug and cd26, which is applied in the field of prodrug of hiv inhibitory compounds, can solve the problems of unsatisfactory physicochemical and biopharmaceutical properties of many existing drug molecules already on the market, unrealized medical advances, and unfavorable new chemical structures. , to achieve the effect of convenient preparation, and reducing the risk of infection

Inactive Publication Date: 2008-09-04
DE KOCK HERMAN AUGUSTINUS +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The invention provides a new prodrug technology that can improve the solubility and bioavailability of therapeutic compounds. This technology involves the use of prodrugs that are cleavable by dipeptidyl-peptidases, such as CD26, which are enzymes found in the body. The prodrugs are made by attaching a therapeutic compound to an oligopeptide consisting of a general structure. The oligopeptide can have between two to five CD26 cleavable repeats. The therapeutic compound can be an antiviral drug, in particular an inhibitor of HIV protease. The prodrug can be administered to a patient to improve its solubility, bioavailability, and target specific sites in the body."

Problems solved by technology

However, it is rather common that these novel chemical structures have unfavourable physicochemical and biopharmaceutical properties.
Moreover, the physicochemical properties of many existing drug molecules already on the market are not optimal.
Today, drug candidates are often discontinued due to issues of poor water solubility or inadequate absorption, leaving countless medical advances unrealized.
Still other products make it to the market, but never realize their full commercial potential due to safety or efficacy concerns.
These oligonucleotides and intercalators have not to be released after cell penetration however, and can not be regarded as prodrugs.

Method used

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  • Hiv Prodrugs Cleavable by Cd26
  • Hiv Prodrugs Cleavable by Cd26
  • Hiv Prodrugs Cleavable by Cd26

Examples

Experimental program
Comparison scheme
Effect test

example 1

Val-Pro-PI 1

[0174]Step 1

[0175]Compound 1.1 (0.95 g; 1.69 mmol) and Boc-Val-Pro-OH (0.53 g; 1.7 mmol) were dissolved in 10 ml N,N-dimethylformamide. EDCI (0.36 g; 1.9 mmol) and HOAt (0.023 g; 0.17 mmol) were added and stirred at room temperature for 20 hours. The reaction mixture was poured in H2O and extracted twice with ethylacetate. The combined organic layer was washed with brine and then dried over Na2SO4. Solvent was removed and the obtained crude product purified by column chromatography (eluent:ethylacetate). Compound 1.2 was obtained as a white solid (yield 55%, purity 95% LC-MS).

[0176]Step 2

[0177]To a solution of compound 1.2 (0.77 g; 0.9 mmol) in 10 ml CH2Cl2 was added 10 ml trifluoroacetic acid. After stirring the reaction mixture at room temperature for 3 hours, the solvent was removed. The crude mixture was purified by column chromatography yielding 0.42 g of compound 1.3 (yield 61%, purity 95% LC-MS)

example 2

Asp-Pro-PI 1

[0178]Step 1

[0179]Compound 2.1 (3.16 g; 5.63 mmol) and Boc-Pro-OH (1.33 g; 6.18 mmol) were dissolved in 30 ml N,N-dimethylformamide. EDCI (1.18 g; 6.18 mmol) and HOAt (0.077 g; 0.5 mmol) were added and stirred for 36 hours. Ethylacetate and 0.1 N HCl were added and the resulting reaction mixture was extracted 3 times with ethylacetate. The combined organic layer was washed with 0.1 N HCl, H2O, saturated NaHCO3, water and brine. After drying over Na2SO4 and evaporation of the solvent a white foam (4.39 g, 103%) was obtained. After trituration in diisopropylether, 3.9 g of compound 2.2 was obtained (yield 93%, purity 97% LC-MS)

[0180]Step 2

[0181]A mixture of compound 2.3 (3.7 g, 4.8 mmol) and 15 ml trifluoroacetic acid in 40 ml CH2Cl2 was stirred at room temperature for 2 hours. After evaporation of solvent the crude sure was partitioned between ethylacetate and saturated NaHCO3. The organic layer was separated, washed with brine and dried over Na2SO4. Re-slurry of the crud...

example 3

Asp-Pro-Lys-Pro-PI 1

[0186]

[0187]Using analogous reaction procedures as described in examples 1 and 2, Boc-Lys(Fmoc)-OH was coupled to compound 3.1 (as prepared in example 2), yielding compound 3.2. After Boc-deprotection, compound 3.3 was obtained. Boc-Pro-OH was then coupled to compound 3.3, yielding compound 3.4 which was subsequently Boc-deprotected thus yielding compound 3.5. Compound 3.5 was coupled with Boc-Asp(OtBu)-OH yielding compound 3.6 which was first Boc-deprotected and then Fmoc-deprotected using dimethylamine in tetrahydrofuran, thus yielding compound 3.8 corresponding to Asp-Pro-Lys-Pro-PI 1.

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Abstract

The present invention provides new prodrugs which are conjugates of a therapeutic compound and a peptide wherein the conjugate is cleavable by dipeptidyl-peptidases, more preferably by CD26, also known as DPPIV (dipeptidyl aminodipeptidase IV). The present prodrugs have the formulathe stereoisomeric forms and salts thereof, wherein n is 1 to 5; Y is proline, alanine, hydroxyproline, dihydroxyproline, thiazolidinecarboxylic acid (thioproline), dehydroproline, pipecolic acid (L-homoproline), azetidinecarboxylic acid, aziridinecarboxylic acid, glycine, serine, valine, leucine, isoleucine and threonine; X is selected from any amino acid in the D- or L-configuration; X and Y in each repeat of [Y-X] are chosen independently from one another and independently from other repeats; Z is a direct bond or a bivalent straight or branched saturated hydrocarbon group having from 1 to 4 carbon atoms; R1 is an aryl, heteroaryl, aryloxy, heteroaryloxy, aryloxyC1-4alkyl, heterocycloalkyloxy, heterocycloalkylC1-4alkyloxy, heteroaryloxyC1-4alkyl, heteroarylC1-4alkyloxy; R2 is arylC1-4alkyl; R3 is C1-10alkyl, C2-6alkenyl or C3-7cycloalkylC1-4alkyl; R4 is hydrogen or C1-4alkyl. The present invention furthermore provides the use of said prodrugs as medicines as well as a method of producing said prodrugs.

Description

FIELD OF THE INVENTION[0001]The invention relates to prodrug of HIV inhibitory compounds whereby the HIV inhibitory compound is released or activated by proteolysis of a peptidic moiety. The invention also relates to methods for increasing oral uptake, modify serum protein binding, blood-brain barrier penetration or solubility and bioavailability of the HIV inhibitory compounds.BACKGROUND OF THE INVENTION[0002]Modern drug discovery techniques (e.g. combinatorial chemistry, high-throughput pharmacological screening, structure-based drug design) are providing very specific and potent drug molecules. However, it is rather common that these novel chemical structures have unfavourable physicochemical and biopharmaceutical properties. Besides, during the development of new therapeutic agents, researchers typically focus on pharmacological and / or biological properties, with less concern for physicochemical properties. However, the physicochemical properties (dissociation constant, solubili...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/40C07D493/04C07D207/12A61P31/18A61K31/34A61K38/00A61K47/48C07H15/252C07K5/06C07K5/062C07K5/065C07K5/068C07K5/072C07K5/083C07K5/103C07K5/11C07K5/113C07K7/06C07K9/00
CPCA61K38/00A61K47/48246C07D493/04C07H15/252C07K5/06052C07K5/06113C07K9/003C07K5/1008C07K5/101C07K5/1019C07K5/1021C07K7/06C07K5/0808A61K47/64A61P11/00A61P15/00A61P25/00A61P25/04A61P25/24A61P29/00A61P3/00A61P3/10A61P31/04A61P31/10A61P31/12A61P31/18A61P33/02A61P3/04A61P37/00A61P37/08A61P43/00A61P9/00A61K47/50C07C311/17C07C311/29C07D207/00
Inventor DE KOCK, HERMAN AUGUSTINUSWIGERINCK, PIET TOM BERT PAULBALZARINI, JAN
Owner DE KOCK HERMAN AUGUSTINUS
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