GnRh antagonists being modified in positions 5 and 6

An antagonist, hormone technology, applied in the field of decapeptide, an antagonist of human gonadotropin-releasing hormone, inhibiting excessive secretion of gonadal steroids

Inactive Publication Date: 2000-07-12
FERRING BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Despite the attractive properties of this group of GnRH antagonists, research continues on GnRH antagonists with improved properties, especially those with prolonged biological action

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] It was found that a peptide of the formula: Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-Lys(Nic)-D-Lys(Nic)-Leu-ILys-Pro-D-Ala-NH 2 (Antiide), has a very good biological activity as a GnRH antagonist, and the peptide currently known as Axilin also has this activity and the difference from Antiide is only at the 5th and 6th positions. It has now been found that using these molecules as a starting point and by making additional substitutions at positions 5 and 6, or at position 5 of the decapeptide asicillin, GnRH antagonists with longer duration of biological activity in vivo can be obtained. For positions 1-4 and 7-10, it should be noted that Antidote, Axiline and Azaline are all identical.

[0086] By solid-phase synthesis, the following decapeptides [4Aph(Hor) 5 , D-4Aph (Cbm) 6 ]-antide or [Ac-D-2Nal 1 , D-4Cpa 2 , D-3Pal 3 , 4Aph(Hor) 5 , D-4Aph (Cbm) 6 , Ilys 8 , D-Ala 10 ]-GnRH. This peptide has the following formula:

[0087] Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(L-hydroor...

Embodiment 1A

[0101] Repeat the synthesis process described in Example 1, and use N α Boc-D-4Amf(Fmoc) replaces N α Boc-D-4Aph (Fmoc). After deprotection of the D-4Amf side chain, the reaction with tert-butyl isocyanate was performed as before. Peptides were cleaved from the resin and deprotected as described in Example 1, followed by purification. The peptide Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(L-hydroorotoyl)-D-Amf(carbamoyl)-Leu-Lys(isopropyl Base)-Pro-D-Ala-NH 2 , which was then evaluated and found to be substantially homogeneous with an estimated purity greater than 99%. MS analysis indicated a molecular weight of 1645.9 Da, which is very close to the predicted molecular weight of 1645.8 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than ascillin.

[0102] Testing of this peptide in a standard in vivo rat LH suppression test showed that at a dose of 50 micrograms, it suppressed LH levels as effectively as acillin at 1, 2, and 3 days. At 96 hours, L...

Embodiment 1B

[0104] In order to form the analog [4Aph(Hor) 5 ]-azillin, the synthesis process described in Example 1 was repeated, and tert-butyl isocyanate was replaced with acetic anhydride when reacting with the deprotected 6-position side chain. Peptides were cleaved from the resin and deprotected as described in Example 1, followed by purification. The peptide Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(L-hydroorotoyl)-D-4Aph(acetyl)-Leu-Lys(isopropyl )-Pro-D-Ala-NH 2 . The peptide was evaluated to be substantially homogeneous with an estimated purity greater than 99%. MS analysis indicated a molecular weight of 1630.6 Da, which is consistent with the calculated molecular weight of 1630.8 Da.

[0105] The peptide was tested as in Example 1 in a standard in vivo rat test. The results showed that at a dose of 50 micrograms, the peptide was biologically active and was nearly as effective as acillin on days 1-4. This peptide is considered to be very long-acting for inhibiting LH.

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PUM

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Abstract

Peptides are provided which have improved duration of GnRH antagonistic properties. These antagonists may be used to regulate fertility and to treat steroid-dependent tumors and for other short-term and long-term treatment indications. These antagonists have a derivative of aminoPhe or its equivalent in the 5- or the 5- and 6-positions. This derivative is modified so as to contain a carbamoyl group or heterocycle, including a urea moiety, in its side chain. Decapeptides having the formula:wherein Q2 is Cbm or MeCbm and Xaa10 is D-Ala-ol or Ala-ol are particularly effective and continue to exhibit very substantial suppression of LH secretion at 96 hours following injection.

Description

[0001] The present invention generally relates to a class of peptides which are antagonists of human gonadotropin releasing hormone (GnRH) and possess advantageous physical, chemical and biological properties. More specifically, the present invention relates to decapeptides, which inhibit gonadal function and the long-term release of the steroid hormones progesterone and testosterone, and to the administration for this purpose of pharmaceutical compositions containing the decapeptides, in particular for the inhibition of gonadal steroid Hypersecretion. Background of the invention [0002] Follicle-stimulating hormone (FSH) and luteinizing hormone (LH), sometimes called gonadotropins or gonadotropins, are released by the pituitary gland, which is connected to the hypothalamus through a stalk. [0003] The release of hormones from the anterior pituitary usually requires the release of hormones produced by the hypothalamus first, such as GnRH decapeptide. [0004] Inhibition of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/04A61K38/00A61K38/09A61K49/00A61P5/02A61P5/24A61P15/00A61P15/08A61P35/00A61P43/00C07K7/06C07K7/23
CPCA61K38/00Y10S930/11C07K7/23Y10S514/80Y02P20/55A61P15/00A61P15/08A61P35/00A61P43/00A61P5/02A61P5/24A61K38/09
Inventor G·森普尔姜广成
Owner FERRING BV
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