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FPR1 antagonist derivatives and use thereof

a technology of fpr1 and derivatives, applied in the field of dipeptide derivatives, can solve problems such as inability to inhibi

Inactive Publication Date: 2015-04-09
CHANG GUNG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 2010, Movitz and his co-workers showed that a peptide with a Trp-Phe fragment in the C-terminal was able to selectively bind to the FPR1 receptor; however, this dipeptide alone was unable to inhibit the neutrophil respiratory burst induced by FMLP, and the associated generation of superoxide anion (O2•-) or radicals.

Method used

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  • FPR1 antagonist derivatives and use thereof
  • FPR1 antagonist derivatives and use thereof
  • FPR1 antagonist derivatives and use thereof

Examples

Experimental program
Comparison scheme
Effect test

embodiment 1

General Procedure for the Synthesis of N—(N-aroyl-L-tryptophanyl)-D-phenylalanine methyl esters (compounds 3-7) and their analogs (compounds 8-10, 11a and 11 b)

[0074]To a mixture solution of L-tryptophan (2a, 1.0 equiv.) or 5-hydroxy-L-tryptophan (2b, 1.0 equiv.) in 2 N NaOH aqueous solution was added suitable acyl chlorides (1.1 equiv.), respectively. The reaction mixture was stirred at room temperature for 3.0 h, and then 1 N HCl solution was added and the pH values were adjusted to 1-2. The mixture solution was further partitioned by chloroform, and the organic layer was evaporated at reduced pressure to yield intermediates. The intermediates and D-phenylalanine methyl ester (1.0 mmole) were dissolved in DCM, and then HBTU (2.0 equiv.) and DIEA (1.5 equiv.) were added. The reaction mixture was stirred for 6 hours at room temperature, concentrated, and purified by silica gel column chromatography using a mixture of n-hexane-ethyl acetate (6:4) or n-hexane-acetone (7:3), respective...

embodiment 2

General procedure for the synthesis of N—(N-benzoyl-L-tryptophanyl)-D-phenylalaninol derivatives (compounds 12a-13a and 12b-13b)

[0085]N-Benzoyl-L-tryptophan and N-benzoyl-5-hydroxy-L-tryptophan were obtained by a similar procedure as described above. Dissolve N-benzoyl-L-tryptophan (1.0 equiv.) or N-benzoyl-5-hydroxy-L-tryptophan (1.0 equiv.) in DCM respectively, and then D-phenylalaninol (1.0 equiv.), HBTU (2.0 equiv.) and DIEA (1.5 equiv.) were added. The reaction mixture was stirred at room temperature for 6.0 h, and purified by silica gel column chromatography using ethyl acetate or MeOH—CHC13 (1:20) to afford the mixtures 12a / b and 13a / b. The mixture was further purified by HPLC (mobile phase: 35% acetonitrile+0.3% TFA) to afford products.

N—(N-Benzoyl-L-tryptophanyl)-5-hydroxy-D-phenylalaninol (compounds 12a and 12b)

Compound 12a

[0086]16% yield. White powder, mp 175-177° C. 1H NMR (C5D5N) δ 11.77 (1H, s, NH), 8.97 (1H, d, J=8.0 Hz, NH), 8.88 (1H, d, J=8.0 Hz, NH), 8.05 (2H, d, J...

embodiment 3

Preparation of N—(N-nicotinoyl-L-tryptophanyl)-D-phenylalanine methyl esters (compounds 15a and 15b)

[0090]A mixture solution of L-tryptophan methyl ester (1.0 equiv.) in pyridine and nicotinoyl chlorides (1.1 equiv.) was prepared. The reaction mixture was stirred at room temperature for 16.0 h, and then evaporated and purified by silica gel column chromatography using a mixture of MeOH—CHCl3 (1:20) to afford N-nicotinoyl-L-tryptophan methyl ester. N-Nicotinoyl-L-tryptophan methyl ester was further dissolved in 10 mL of 1.0 M LiOH solution, and then added to the mixture for hydrolysis. Upon completion, the reaction mixture was partitioned for three times with ethyl acetate and saturated sodium bicarbonate aqueous solution. The combined aqueous layer was neutralized with 1.0 N HCl solution, followed by extraction with ethyl acetate for three times. The combined organic layer was dried with anhydrous magnesium sulfate and evaporated to yield N-nicotinoyl-L-tryptophan. D-Phenylalanine m...

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Abstract

A dipeptide derivative as formyl peptide receptor 1 (FPR1) antagonist is provided. The dipeptide derivative is represented by formula (I),wherein:the chiral centers in formula (I) are S and R configurations respectively;each of RK and RT is selected from a group consisting of a hydrogen, a hydroxyl group, a C1-C4 alkyl-substituted hydroxyl group, a C1-C4 alkoxyl group, a carboxylic acid group, a C1-C4 alkyl nitrile-substituted, C1-C4 alkyl-substituted or C1-C4 alkoxyl-substituted amido group, a C1-C4 alkyl-substituted ester group and a benzoyl group having a C1-C4 alkyl-substituted benzene ring; and each of RM and RS is selected from a group consisting of a hydrogen, a hydroxyl group, a phenyl group, a pyridinyl group, a carboxylic acid group, a C1-C4 alkoxyl substituted ester group, and a benzoyl group having a hydroxyl-substituted, a halogen-substituted, a C1-C4 alkoxyl-substituted or a C1-C4 alkyl-substituted benzene ring.

Description

CROSS-REFERENCE TO RELATED APPLICATION AND CLAIM OF PRIORITY[0001]This application claims the benefit of Taiwan Patent Application No. 102136641, filed on Oct. 9, 2013, at the Taiwan Intellectual Property Office, the disclosures of which are incorporated herein in their entirety by reference.FIELD OF THE INVENTION[0002]The present invention relates to the use of dipeptide derivatives, such as N—(N-aroyl-L-tryptophanyl)-D-phenylalanine methyl esters and their applications in diseases or symptoms associated with formyl peptide receptor 1 (FPR1) activities.BACKGROUND OF THE INVENTION[0003]Formyl peptide receptor (FPR) belongs to the family of G-protein coupled receptors (GPCRs). The FPR family can be divided into three classes, FPR1, FPR2 and FPR3. FPR2 and FPR3 are classified into FPR-like receptors, wherein FPR2 is also known as FPR-like receptor 1 (FPRL-1) and FPR3 is also known as FPR-like receptor 2 (FPRL-2). FPR1 is found in monocytes, polymorphonuclear leukocytes and immature de...

Claims

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Application Information

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IPC IPC(8): C07K5/065C07D209/20
CPCC07D209/20C07K5/06078C07K5/06156A61K38/00A61P29/00
Inventor HWANG, TSONG-LONGHSIEH, PEI-WENHUANG, YIN-TINGHUNG, CHIH-HAO
Owner CHANG GUNG UNIVERSITY
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