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Ghrelin analogs

A compound, -A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A20-A21-A22 - The technology of A23-A24-A25-A26-A27-A28-R1 is applied in the direction of hormone peptides, animal/human proteins, peptide/protein components, etc., and can solve the problem of low oral bioavailability and stimulation of peptidyl growth hormone secretagogue Non-peptide compound research and other issues

Inactive Publication Date: 2006-09-13
SOC DE CONSEILS DE RECH & DAPPLICATIONS SCI SAS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The low oral bioavailability of peptidyl growth hormone secretagogues stimulates the investigation of non-peptidic compounds that mimic the actions of GHRP-6 in the pituitary

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0882] Embodiment 1: (Glu 3 (O-hexyl))hGhrelin(1-28)-NH 2

[0883] The title peptide was synthesized on an Applied Biosystems (Foster City, CA) Model 433A Peptide Synthesizer. 4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamide-norleucyl-MBHA resin (Rink Amide MBHA resin) with 0.72mmol / g substituent was used , Novabiochem, San Diego, CA). Fmoc amino acids (AnaSpec, San Jose, CA) with the following side chain protections were used: Fmoc-Arg(Pbf)-OH, Fmoc-Pro-OH, Fmoc-Gln-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc )-OH, Fmoc-Ala-OH, Fmoc-Ser(tBu)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Val-OH, Fmoc-His(Trt)-OH, Fmoc-Phe-OH, and Fmoc-Asp(OtBu)-OH. Boc-Gly-OH (Midwest Bio-Tech, Fishers, IN) was used in position 1. N-α-Fmoc-L-glutamic acid γ-4-{N-(1-(4,4-Dimethyl-2,6-dioxocyclohexylene)-3-methylbutyl)-amino } Benzyl ester (Fmoc-Glu(ODmab)-OH) (Chem-Inpex International, WoodDale, IL) was used at position 3. Synthesis was performed on a 0.25 mmol scale. The Fmoc group was removed by treatment...

Embodiment 2

[0885] Embodiment 2: (Aib 2 )hGhrelin(1-28)-NH 2

[0886] According to the synthesis described in Example 1 (Glu 3 (O-hexyl))hGhrelin(1-28)-NH 2 The title peptides were synthesized by the method described above, except for the following: Fmoc-Ser-OH for position 3, Fmoc-Aib-OH for position 2, and Boc-Gly-OH for position 1. After assembly of the peptide chains, the peptide-resin was treated with 25% piperidine in DMF for 3 x 2 h. The resin was washed with DMF and treated with octanoic acid (2.5 mmol, 10-fold excess), HBTU (2.2 mmol), HOBt (2.2 mmol) and DIEA (7.5 mmol) in DMF for 2 h. The resin was washed with DMF and treated with octanoic acid (2.5 mmol), DIC (2.5 mmol), HOBt (2.5 mmol) and DMAP (0.025 mmol) in DMF for 2 h. The final cleavage and purification steps are the same as in Example 1. Analytical HPLC determined that the product was homogeneous with a purity of 99% and a yield of 18.5%.

[0887] The molecular weight of the surface product analyzed by electrospr...

Embodiment 3

[0888] Embodiment 3: (Glu 3 (NH-hexyl))hGhrelin(1-28)-NH 2

[0889] The title peptide was synthesized on an Applied Biosystems (Foster City, CA) Model 430A Peptide Synthesizer modified for accelerated Boc-chemical solid-phase peptide synthesis, see Schnolzer, et al., Int. J. Ppetide Protein Res., 40:180 (1992 ). 4-Methylbenzhydrylamine (MBHA) resin (Peninsula, Belmont, CA) with 0.91 mmol / g substituent was used. Boc amino acids (Midwest Bio-Tech, Fishers, IN; Novabiochem, San Diego, CA) with the following side chain protections were used: Boc-Ala-OH, Boc-Arg(Tos)-OH, Boc-His(DNP)-OH , Boc-Val-OH, Boc-Leu-OH, Boc-Gly-OH, Boc-Gln-OH, Boc-Lys(2ClZ)-OH, Boc-Ser(Bzl)-OH, Boc-Phe-OH, Boc -Glu(OcHex)-OH and Boc-Pro-OH. Position 3 in the residue sequence used Fmoc-Glu(OtBu)-OH (Novabiochem, San Diego, CA). Synthesis was performed on a scale of 0.25 mmol. Treat with 100% TFA for 2×1 min to remove the Boc group. Boc amino acids (2.5 mmol) were preactivated with HBTU (2.0 mmol) an...

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Abstract

The invention comprises peptidyl analogs that possess agonist or antagonist ghrelin activity, along with therapeutic and non-therapeutic uses thereof.

Description

Background technique [0001] The intermittent release of growth hormone from pituitary somatotroph cells is regulated by two hypothalamic neuropeptides, growth hormone releasing hormone and somatostatin. Growth hormone releasing hormone stimulates the release of growth hormone, whereas somatostatin inhibits growth hormone secretion (Frohman et al., Endocronol. Rev. 1986, 7, 223-253, and Strobi et al., Pharmacol. Rev. 1994, 46 , 1-34). [0002] Growth hormone release from pituitary somatotroph cells can also be controlled by ghrelin. found that the hexyl peptide His-D-Trp-Ala-Trp-D-Phe-Lys-amide (GHRP-6) released growth hormone from somatotrops in a dose-dependent manner in several species including humans ( Bowers et al., Endocrinology 1984, 114, 1537-1545). Other potent growth hormone secretagogues, such as GHRP-1, GHRP-2 and hexarelin (Cheng et al., in Endocrinology 1989, 124, 2791- 2798; Bowers, C.Y. Novel GH-Releasing Peptides, In Molecular and Clinical Advances in Pitu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/16C07K14/00C07K14/575
Inventor 董正欣怡兰娜·沈
Owner SOC DE CONSEILS DE RECH & DAPPLICATIONS SCI SAS
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