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Polypeptide compound and application thereof

A technology of peptide compounds and stereoisomers, applied in the field of peptide compounds and their applications

Pending Publication Date: 2022-07-29
CHENGDU SINTANOVO BIOTECHNOLOGV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] By analyzing the structure of GHRP6, some GHRP analogues have been found, which can combine with GHSR-1a to produce agonistic activity, cause signal transduction, and regulate the secretion of growth hormone, but they all have certain limitations in clinical development.

Method used

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  • Polypeptide compound and application thereof
  • Polypeptide compound and application thereof
  • Polypeptide compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1～54

[0138] Preparation of compounds 1-54

[0139] Polypeptide synthesis adopts standard Fmoc solid-phase method, selects Rink Amide resin, binds the C-terminal amino acid to the resin, and extends the peptide chain from the C-terminal to the N-terminal. The protected amino acids used in the present invention include: Fmoc-Apc(Boc)-OH, Fmoc-D-Lys(Boc)-OH, Fmoc-D-Orn(Boc)-OH, Fmoc-Phe-OH, Fmoc-D-Trp (Boc)-OH, Fmoc-D-Bal-OH, Fmoc-D-Cit-OH, Fmoc-D-Arg(Pbf)-OH, Boc-D-Aba-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Alloc)-OH, Fmoc-Gly-OH, Fmoc-D-Ala-OH, Fmoc-D-Val-OH, Fmoc-D-Leu-OH, Fmoc-Pro-OH, Fmoc-β-Ala -OH, Fmoc-D-Tle-OH, Fmoc-Tle-OH, Fmoc-D-Nle-OH, Fmoc-Nle-OH, cis-2-(tert-butoxycarboxamide)-1-cyclopentanecarboxylic acid , Boc-methyl-1-(aminomethyl)cyclobutanecarboxylic acid, 1-N-Boc-3-azetidinecarboxylic acid, Boc-3-aminooxetane-3-carboxylic acid, 1- Boc-D-acridine-2-carboxylic acid, (S)-1-Boc-pyrrolidine-3-carboxylic acid, Boc-2-morpholinecarboxylic acid, (Boc-3-amino-1-adamantane)acetic a...

Embodiment 55

[0161] The agonistic activity evaluation experiment of polypeptide compounds on GHSR-1a (EC 50 )

[0162] Screening of GHSR-active compounds is accomplished by recombinantly expressing the receptor. The use of recombinant expression of GHSR offers several advantages, such as the ability to express the receptor in a defined cellular system so that the response of a compound to GHSR can be more easily distinguished from that of other receptors. For example, GHSR can be expressed in cell lines such as HEK293, COS7, and CHO that normally express GHSR without an expression vector, and the same cell line without an expression vector can be used as a control.

[0163] The activity of GHSR-1a can be measured using different techniques, eg, by detecting changes in the intracellular conformation of GHSR-1a, changes in G-protein coupling activity, and / or changes in intracellular messengers, among others. Preferably, methods such as measuring intracellular Ca 2+ technique to measure GH...

Embodiment 56

[0193] Inhibition of Cytochrome P450 Oxidase (CYP450) by Polypeptide Compounds

[0194] The metabolism of drugs in vivo can be divided into phase I reactions (catabolism) and phase II reactions (anabolism). Phase I reactions include oxidation, reduction and hydrolysis reactions, mainly catalyzed by cytochrome P450 (CYP450) enzymes. CYP450 enzymes are mainly distributed in the liver, so they are also called liver drug enzymes. Induction and inhibition of CYP450 enzymes have important clinical implications and can lead to clinical drug interactions. Therefore, the inhibition experiment of CYP450 is often used as a safety index to evaluate the druggability of drugs.

[0195] Compounds 1 to 44 obtained in Examples 1 to 44 were used as test compounds. Human liver microsomes containing cytochrome P450 (0.253 mg / mL protein) were combined with test compounds (0.05 to 50 μM), CYPs substrate (10 μM p-acetamido) phenol, 5 μM diclofenac, 30 μM mephentoin, 5 μM dextromethorphan hydrobro...

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Abstract

The invention provides a polypeptide compound and an application thereof, and the polypeptide compound or a stereoisomer and a pharmaceutically acceptable salt thereof, the polypeptide compound has a structure as shown in a formula I, and the formula I is U1-A1-A2-A3-U2-W-R1. Experimental results show that the polypeptide compound provided by the invention has relatively high agonistic activity on GHSR-1a, small toxic and side effects and relatively good stability in plasma, and has the potential of becoming a clinical candidate compound.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and particularly relates to a polypeptide compound and its application. Background technique [0002] Growth hormone (GH) is released by the pituitary somatotropin cells, which mainly stimulate the growth of tissues, and at the same time affect the metabolic process, and affect the exchange of carbohydrates to fatty acid metabolism in energy metabolism. Growth hormone release is regulated by two hypothalamic neuropeptides, growth hormone releasing hormone (GHRH), which promotes release, and somatostatin (SS), which inhibits release. ). [0003] Growth hormone releasing peptide (ghrelin) is the endogenous ligand of growth hormone secretagogue receptor (GHSR). Growth Hormone Secretagogue Receptor (GHSR), also known as ghrelin receptor, was successfully screened and isolated from a cDNA library of porcine pituitary gland. It is a G protein-coupled composed of seven transmembrane alpha helices ...

Claims

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Application Information

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IPC IPC(8): C07K7/06A23L33/18A61K38/08A61P3/00A61P5/02G01N33/68
CPCC07K7/06A23L33/18A61P3/00A61P5/02G01N33/6893A23V2002/00A61K38/00G01N2800/04A23V2200/30A23V2250/55
Inventor 孟广鹏袁瑜黄波李元波
Owner CHENGDU SINTANOVO BIOTECHNOLOGV CO LTD
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