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Polypeptide protracting tags

a polypeptide and protracting tag technology, applied in the field of polypeptide protracting tags, can solve the problems of not being suitable for drug candidates, endogenous peptides are not always suitable for endogenous peptides, and the reason for the strong variability of the plasma half-live of peptides, proteins, or other compounds is not well understood, and achieve the effect of increasing the plasma half-life of a molecul

Inactive Publication Date: 2009-04-30
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005]According to the present invention there is provided a method for increasing the plasma half-life of a molecule, comprising covalently linking this molecule to a heterocyclic carboxylic acid bioisostere.
[0006]The present invention also relates to a method for increasing the plasma half-life of a molecule, comprising covalently linking this molecule to a 1H-tetrazole.
[0043]Thus, a considerable effort is being made to develop analogues and derivatives of the polypeptides susceptible to DPP-IV mediated hydrolysis in order to reduce the rate of degradation by DPP-IV.

Problems solved by technology

Currently there are no universally applicable strategies to enhance the plasma half-life of any type of compound.
Endogenous peptides are, however, not always suitable as drug candidates because these peptides often have half-lives of few minutes due to rapid degradation by peptidases and / or due to renal filtration and excretion in the urine.
The reason for this strong variability of plasma half-lives of peptides, proteins, or other compounds is, however, not well understood.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

16-(5-tetrazolyl)hexadecanoic Acid

[0263]

[0264]A mixture of 16-bromohexadecanoic acid (16.61 g, 49.5 mmol), DMSO (150 ml), NaCN (12.5 g, 255 mmol), and NaI (1.92 g, 12.8 mmol) was stirred at 120° C. for 20 h. The mixture was allowed to cool to room temperature, and was then poured into a stirred mixture of water (1.7 l) and concentrated HCl (30 ml). Rinsing with water (100 ml). The resulting suspension was stirred at room temperature overnight. The product was filtered and washed with water (2×100 ml), and the solid was recrystallized twice from MeCN (90 ml and 50 ml). 10.1 g (72%) of 16-cyanohexadecanoic acid was obtained.

[0265]1H NMR (DMSO) δ 1.20-1.39 (m, 22H), 1.50 (m, 4H), 2.18 (t, J=7 Hz, 2H), 2.48 (t, J=7 Hz, 2H), 11.95 (s, 1H).

[0266]This product was mixed with DMF (150 ml), AcOH (10.0 ml, 174.8 mmol), NEt3 (25 ml, 180 mmol), and NaN3 (11.83 g, 182 mmol), and the mixture was stirred at 120° C. for 80 h, while following the conversion by 1H NMR. The mixture was concentrated und...

example 2

4-(N-(16-(5-tetrazolyl)hexadecanoyl)sulfamoyl)butyric Acid

[0268]

[0269]To a suspension of 16-(5-tetrazolyl)hexadecanoic acid (3.25 g, 10.0 mmol) in DCM (40 ml) was added oxalyl chloride (1.2 ml, 14.0 mmol). The mixture was stirred at room temperature for 42 h, concentrated, coevaporated once with PhMe, and to the residue were added a solution of methyl 4-sulfamoyl butyrate (1.66 g, 9.16 mmol) in DCM (35 ml) and then DMAP (3.67 g, 30.0 mmol). The heterogenous mixture was stirred at room temperature for 6.5 h and then concentrated. To the residue was added a mixture of water (50 ml) and 1N HCl (50 ml), and the resulting mixture was stirred at room temperature for 5 d. The product was filtered, washed with water (100 ml), and recyrstallized from MeCN (25 ml), to yield 1.84 g (41%) of the N-acylsulfonamide methyl ester. To this ester (1.06 g, 2.17 mmol) in MeOH (15 ml) was added a solution of NaOH (0.38 g, 9.5 mmol, 4.4 eq) in water (1.5 ml). After stirring at room temperature for 1.5 h ...

example 3

16-(4′-(5-tetrazolyl)biphenyl-4-yloxy)hexadecanoic Acid

[0271]

16-Bromohexadecanoic Acid Methyl Ester

[0272]A mixture of 16-bromohexadecanoic acid (15.5 g, 46.2 mmol), MeOH (100 ml), PhMe (30 ml), trimethylorthoformate (30 ml), and polystyrene-bound benzenesulfonic acid (3.6 g) was stirred at 55° C. After 69 h the mixture was filtered through celite and the filtrate was concentrated to yield 16.85 g of an oil (100% yield).

(4′-Cyanobiphenyl-4-yloxy)hexadecanoic Acid Methyl Ester

[0273]A mixture of 16-bromohexadecanoic acid methyl ester (4.86 g, 13.9 mmol), MeCN (20 ml), 4-cyano-4′-hydroxybiphenyl (3.16 g, 16.2 mmol), and K2CO3 (2.45 g, 17.7 mmol) was stirred at 82° C. After 17 h satd aquous NaHCO3 (150 ml) was added, and the product was filtered, washed with water, and recrystallized from boiling MeCN (approx 80 ml). Filtration and drying under reduced pressure yielded 5.40 g (84%) of (4′-cyanobiphenyl-4-yloxy)hexadecanoic acid methyl ester colorless needles.

16-(4′-(5-Tetrazolyl)biphenyl...

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Abstract

Method for increasing (protracting) half-life of LGP analogs in plasma and novel derivatives of such peptides based on covalently linking them to a tetrazole moiety which acts as a carboxylic acid bioisostere.

Description

FIELD OF THE INVENTION[0001]The present invention relates to compounds comprising a heterocyclic carboxylic acid bioisostere, methods for preparing the compounds and the medical applications of such compounds.BACKGROUND OF THE INVENTION[0002]It is often desirable to maintain well-defined concentrations of a given compound in the blood stream for a long time. This would for instance be the case when an immunogen is administered and a strong immune response is desired, or when a therapeutic target has to be exposed continuously to a therapeutic agent for a long time. Currently there are no universally applicable strategies to enhance the plasma half-life of any type of compound. The number of known endogenous polypeptides with interesting biological activities is growing rapidly, also as a result of the ongoing exploration of the human genome. Due to their biological activities, many of these polypeptides could in principle be used as therapeutic agents. Endogenous peptides are, howev...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/48C07D257/04C07K1/00A61P3/00
CPCA61K47/48061A61K47/48023A61K47/54A61K47/545A61K38/27A61K31/41C07D257/04A61P1/00A61P1/04A61P25/00A61P25/28A61P29/00A61P3/00A61P3/10A61P3/04A61P3/06A61P3/08A61P5/00A61P9/00A61P9/10A61P9/12A61K31/4164C07K1/113C07K1/006C07K14/61
Inventor DORWALD, FLORENCIO ZARAGOZASCHIODT, CHRISTINE BRUUNHANSEN, THOMAS KRUSEMADSEN, KJELD
Owner NOVO NORDISK AS
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