Human glucagon-like peptide-1 mimics and their use in the treatment of diabetes and related conditions

a technology of glucagon-like peptides and mimics, which is applied in the field of human glucagon-like peptides and their use in the treatment of diabetes and related conditions, can solve the problems of short serum half-life of such peptides and the significant problem of therapy involving the use of glp-1-type molecules, and achieve the effect of increasing high density lipoprotein levels and elevating blood levels of fatty acids

Inactive Publication Date: 2007-12-13
BRISTOL MYERS SQUIBB CO
View PDF46 Cites 66 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0057] In accordance with the present invention, the synthetic isolated peptides described herein possess the ability to mimic the biological activity of GLP peptides, with preference for mimicking GLP-1. These synthetic peptide GLP-1 mimics exhibit desirable in-vivo properties, thus making them ideal therapeutic candidates for oral or parenteral administration.
[0060] Further provided is a method for treating or delaying the progression or onset of diabetes, especially type II diabetes, including complications of diabetes, including retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, atherosclerosis and hypertension, and for increasing high density lipoprotein levels, wherein a therapeutically effective amount of a polypeptide of formula I is administered to a mammalian, e.g., human, patient in need of treatment.

Problems solved by technology

Presently, therapy involving the use of GLP-1-type molecules has presented a significant problem because the serum half-life of such peptides is quite short.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Human glucagon-like peptide-1 mimics and their use in the treatment of diabetes and related conditions
  • Human glucagon-like peptide-1 mimics and their use in the treatment of diabetes and related conditions
  • Human glucagon-like peptide-1 mimics and their use in the treatment of diabetes and related conditions

Examples

Experimental program
Comparison scheme
Effect test

example 1

Simultaneous Solid Phase Peptide Synthesis of GLP-1 11-Mer Peptide Mimics

[0103] Dipeptidyl resin, containing non-natural non-commercial amino acid residues at positions 10 and 11, was prepared using the following manual procedure in a batch-wise mode before continuing peptide chain elongation utilizing the automated simultaneous synthesis protocol on the MPS-396 peptide synthesizer. The synthesis of the Nα-Fmoc-protected biphenylalanine derivatives used in the manual couplings is described in Examples 8-10.

[0104] An amount of 4-(2′,4′-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetyl-p-methyl benzhydrylamine resin (Rink amide MBHA resin; loading: 0.5 mmol / g) sufficient to synthesize several 1′-mer analogs, was swelled by washing with DMF (4×10 mL / g, 5 minutes). The Fmoc group was then removed using two treatments, 3 and 18 minutes each respectively, with 20% piperidine in DMF (10 mL / g). The resin was washed with DMF (4×10 mL / g) and NMP (4×10 mL / g). A 0.5 M solution of Fmoc-L-bipheny...

example 2

Synthesis of N-Acylated and N-Alkylated 11-Mer Peptide Analogs

(A) General Procedure for the Synthesis of N-Alkylated 11-Mer Peptide Analogs by Reductive Alkylation

[0119] The synthesis of N-alkylated 11-mer peptide analogs was started from the protected intermediate 11-mer peptidyl-resin (1) (0.025 mmol), which was prepared by the general method described herein. The Fmoc group was removed using the procedure described in that method, to yield the protected resin intermediate 2. This was swollen in DMF, washed 3 times with 1% AcOH / DMF, and then treated with 2-20 eq. of aldehyde or N-Boc-protected aminoaldehyde (see synthesis below), dissolved in 1% AcOH / DMF (or CH2Cl2) (1 M), and the same excess amount of Na(AcO)3BH as that of the aldehyde. After overnight reaction, the resin was drained, washed with DMF and DCM, 3 times each, and dried. The reductively alkylated peptide (4) was cleaved and deprotected by treatment with TFA / tri-isopropylsilane / water (90:5:5, v:v:v; 1-2 mL) for 2 h...

example 3

Synthesis of N-Arylalkyl Amides of 10-Mer Peptide Analogs

[0126] The synthesis of N-arylalkyl amides of 10-mer peptide analogs was started with a reductive alkylation reaction of a relevant arylalkylamine with an alkoxybenzaldehyde resin as in the following example. 2-(3,5-Dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene resin (Novabiochem, 1.12 mmol / gram, 0.025 mmol, 27.3 mg) was washed with 1% Acetic Acid in DCM (5×3 mL). A solution of 2-(2-pentafluorophenyl)ethyl amine (0.125 mmol, 26.4 mg) in DCM (3 mL) was added to the resin. After 5 minutes, solid NaBH(OAc)3 (0.125 mmol, 26.5 mg,) was added and the reaction was vortexed for 16 hours. The resin was rinsed with DMF (5×3 mL) and DCM (5×3 mL).

[0127] A solution of Fmoc-[BIP(2-Et)]-OH (0.05 mmol, 25.3 mg) and HOAt (0.05 mmol, 6.81 mg) in NMP(0.5 mL) was added to the resin followed by DIC (0.05 mmol, 7.82 μL). The reaction was vortexed for 16 hrs. The resin was rinsed with NMP(5×3 mL). The remaining sequence of the desired 10-mer ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
flow rateaaaaaaaaaa
pressureaaaaaaaaaa
flow rateaaaaaaaaaa
Login to view more

Abstract

The present invention provides novel human glucagon-like peptide-1 (GLP-1) peptide mimics that mimic the biological activity of the native GLP-1 peptide and thus are useful for the treatment or prevention of diseases or disorders associated with GLP activity. Further, the present invention provides novel, chemically modified peptides that not only stimulate insulin secretion in type II diabetics, but also produce other beneficial insulinotropic responses. These synthetic peptide GLP-1 mimics exhibit increased stability to proteolytic cleavage making them ideal therapeutic candidates for oral or parenteral administration.

Description

[0001] This application is a divisional of U.S. application Ser. No. 10 / 273,975, filed Oct. 18, 2002, which claims the benefit of U.S. Provisional Application Ser. No. 60 / 342,015, filed Oct. 18, 2001. Each of the priority applications are incorporated by reference in their entireties.FIELD OF THE INVENTION [0002] The present invention provides novel human glucagon-like peptide-1 (GLP-1) peptide mimics, which duplicate the biological activity of the native peptide, exhibit increased stability to proteolytic cleavage as compared to GLP-1 native sequences, and thus are useful for the amelioration of the diabetic condition. BACKGROUND OF THE INVENTION [0003] GLP-1 is an important gut hormone with regulatory function in glucose metabolism and gastrointestinal secretion and metabolism. Human GLP-1 is a 30 amino acid residue peptide originating from preproglucagon, which is synthesized for example, in the L-cells in the distal ileum, in the pancreas and in the brain. Processing of preprogl...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/10A61K38/05A61K38/06A61P3/00C07K7/00C07K7/08C07K7/06A61P3/10A61K38/07A61K38/08A61K38/00A61K38/26A61K45/06A61P3/04A61P3/06A61P5/50A61P9/10A61P9/12A61P13/12A61P17/02A61P25/00A61P27/02A61P43/00C07K14/00C07K14/605C12N
CPCA61K38/00C07K14/605A61K45/06A61P13/12A61P17/02A61P25/00A61P27/02A61P3/00A61P3/04A61P3/06A61P43/00A61P5/50A61P9/10A61P9/12A61P3/10C07K7/08
Inventor NATARAJAN, SESHA IYERMAPELLI, CLAUDIOBASTOS, MARGARITA M.BERNATOWICZ, MICHAELLEE, VINGEWING, WILLIAM R.
Owner BRISTOL MYERS SQUIBB CO
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap