Dislodgement and release of HSC using alpha 9 integrin antagonist and CXCR4 antagonist

A technology of integrin and antagonist, applied in the direction of peptide/protein components, antineoplastic drugs, medical preparations containing active ingredients, etc., can solve problems such as toxic side effects and long treatment process

Inactive Publication Date: 2017-09-26
COMMONWEALTH SCI & IND RES ORG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although G-CSF is the most widely used mobilizing agent clinically, its disadvantages also include potential toxic side effects, relatively long course of treatment (continuous injection for 5-7 days), and variable responsiveness of patients

Method used

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  • Dislodgement and release of HSC using alpha 9 integrin antagonist and CXCR4 antagonist
  • Dislodgement and release of HSC using alpha 9 integrin antagonist and CXCR4 antagonist
  • Dislodgement and release of HSC using alpha 9 integrin antagonist and CXCR4 antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0484] Example 1: alpha 9 beta 1 Preparation of integrin antagonists

[0485] (a) Synthesis of Antagonist Compounds

[0486] The reagents of the various embodiments can be prepared using the reaction routes and synthetic schemes described below. The preparation of specific compounds of the embodiments is described in detail in the following examples, but the skilled artisan will recognize that the chemical reactions described can be readily adapted to prepare many other reagents of the various embodiments. For example, the synthesis of non-exemplary compounds can be successfully carried out by modifications apparent to those skilled in the art, for example, by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by modifying the reaction conditions Make regular changes. A list of suitable protecting groups in organic synthesis can be found in T.W. Greene's Protective Groups in Organic Synthesis, 3rd edition, John Wiley & ...

Embodiment 1A

[0491] Example 1A: Preparation of N-(benzenesulfonyl)-L-prolyl-L-O-(1-pyrrolidinylcarbonyl)tyrosine (BOP)

[0492] The synthesis of BOP begins with dipeptide 26 as shown in Scheme 1 below:

[0493]

[0494] Process 1

[0495] Deprotection of the tert-butyl protecting group 26 using trifluoroacetic acid at 0°C afforded phenol 27, which was used in the next step without further purification after water workup. The reaction of phenol 27 with 1-pyrrolidinecarbonyl chloride proceeded smoothly in the presence of potassium carbonate, and the carbamate 28 was obtained in good yield (74%) in two steps. The hydrogenolysis of the Cbz protecting group was completed within 3 hours, The amine (85%) was obtained in excellent yield after flash chromatography. The amine 29 was then reacted with benzenesulfonyl chloride in the presence of base to give the sulfonamide 30 (96%) in excellent yield after flash chromatography. Finally, the methyl ester moiety 30 was saponified with sodium hydr...

Embodiment 1B

[0508] Example 1B: Preparation of R-BC154(IXb)

[0509] Compound IXb (R-BC154) lacking the PEG-spacer was also synthesized, as shown in Scheme 2 below:

[0510]

[0511] Process 2

[0512] Therefore, hydrolysis of formate 18 with NaOH gave the deprotected azide inhibitor 23, followed by 4 , sodium ascorbate and TBTA were reacted with N-propynylthiorhodamine B 24 to obtain a fluorescently labeled compound of formula IXb (R-BC154) in 43% yield after purification by HPLC.

[0513] As an example, the actual reaction conditions for the formation of the fluorescently labeled BOP derivative IXb starting from methyl ester 18 are provided herein.

[0514] Step 1: (S)-2-((2S,4R)-4-azido-1-(phenylsulfonyl)pyrrolidine-2-carboxamido)-3-(4-((pyrrolidine- 1-Carbonyl)oxy)phenyl)propionic acid (23)

[0515] Methyl ester 18 (420 mg, 0.737 mmol) in EtOH (10 mL) was treated with 0.2M NaOH (4.05 mL, 0.811 mmol) and stirred at room temperature for 1 hour. The mixture was concentrated under ...

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Abstract

Haematopoietic stem cell mobilization is a process whereby haematopoietic stem cells are stimulated out of the bone marrow space. Before HSC can mobilize, they must be dislodged and released from the BM stem cell niche in which they reside and are retained by adhesive interactions. Accordingly, in an aspect of the present invention there is provided a method for enhancing dislodgement of HSC and their precursors and progenitors thereof from a BM stem cell binding ligand in vivo or ex vivo, said method comprising administering in vivo or ex vivo an effective amount of an antagonist of an alpha9 integrin or an active portion thereof and a CXCR4 antagonist or an active portion thereof to the BM stem cell niche. Once mobilized to the peripheral blood (PB) the HSC may be collected for transplant. Methods which enhance mobilization of the HSC can also improve treatments of haematological disorders.

Description

technical field [0001] The present invention relates to enhancing the migration and release of hematopoietic stem cells (HSCs) and their precursors and progenitors from the bone marrow (BM) stem cell niche, and for enhancing the migration of HSCs and their precursors and their progenitors from the BM and stem cell niches and release method. The present invention also relates to compositions for enhancing the migration and release of HSCs and their precursors and their progenitors. The present invention includes cell populations of HSCs and their precursors and progenitors that have migrated and released by the methods and compositions and the use of said cell populations for the treatment of blood disorders and transplantation of HSCs and their precursors and progenitors . Background of the Invention [0002] HSC regulation and retention within the BM stem cell niche is mediated through interactions between HSC surface receptors and their corresponding ligands expressed by...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K38/17A61K31/401A61P35/00
CPCA61K31/401A61K35/28A61K45/06A61K31/4439A61P35/02A61K31/395A61K38/05A61K2300/00A61K9/0019A61K31/4025
Inventor S·K·尼尔森D·N·海洛克B·B·M·曹
Owner COMMONWEALTH SCI & IND RES ORG
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