US20150099691A1 - Fpr1 antagonist derivatives and use thereof - Google Patents

Fpr1 antagonist derivatives and use thereof Download PDF

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US20150099691A1
US20150099691A1 US14/248,649 US201414248649A US2015099691A1 US 20150099691 A1 US20150099691 A1 US 20150099691A1 US 201414248649 A US201414248649 A US 201414248649A US 2015099691 A1 US2015099691 A1 US 2015099691A1
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substituted
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alkoxyl
benzoyl
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Tsong-Long Hwang
Pei-Wen Hsieh
Yin-Ting Huang
Chih-Hao Hung
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Chang Gung University CGU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06156—Dipeptides with the first amino acid being heterocyclic and Trp-amino acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • 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.
  • 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.
  • Formyl peptide receptor belongs to the family of G-protein coupled receptors (GPCRs).
  • GPCRs G-protein coupled receptors
  • 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 dendritic cells
  • FPR2 is found in liver cells, lung cells, spleen cells, T lymphocytes, monocytes and polymorphonuclear leukocytes.
  • FRP1 and FPR2 are two members of the FPRs, which are found in human neutrophils.
  • Formyl-L-methionyl-L-leucyl-L-phenylalanine fMLP or fMLF
  • fMLP or fMLF is a N-formyl peptide, which is a chemo-attractant bound to FPR1 and further to trigger a cell activating response to release toxic substances or proteases.
  • the affinities of fMLF toward the three FPR receptors are different, and the affinity is higher for FPR1.
  • FPR1 The activation of FPR1 elicits multiple signaling pathways, such as calcium, phospholipase C, phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinases (MAPKs), and protein tyrosine kinases (PTKs), which cause neutrophils activation for migration, respiratory burst, and degranulation.
  • PI3K phosphatidylinositol 3-kinase
  • MAPKs mitogen-activated protein kinases
  • PTKs protein tyrosine kinases
  • FPR1 is not only involved in infection and the inflammatory process, but also playing a role in promoting tumor progression.
  • FPR1 is able to interact with endogenous annexin AI, and then transactivate EGFR in glioblastoma cells to mediate cell migration and growth. Therefore, FPR1 also is a therapeutic target for treating human glioblastoma.
  • EP 2490021 A1 and WO 2012112048 A1 recited a series of dipeptide derivatives containing chemical formulas such as H—X 1 -X 2 —OH, which can be used as pattern recognition receptors and the signal transduction pathway for G-protein coupled receptors, wherein configurations of two amino acids are both S (or R) configurations.
  • US 20130109866 A1 and WO 2013062947 A1 disclose that a series of derivatives of N-terminal amino acids containing urea groups can regulate a FPRL-1 receptor, which is an alias for an FPR2 receptor.
  • WO 2012074785 A1 disclose technical solutions for regulating compounds about FPRL-1 receptors.
  • FPR1 antagonists can regulate inflammation, cancers and other diseases, but no FPR1 antagonist is used clinically. Therefore, the development of an FPR1 antagonist is currently very important.
  • a method for treating neutrophil inflammatory disorders with an antagonist of formyl peptide receptor 1 includes providing a derivative of N—(N-aroyl-L-tryptophanyl)-D-phenylalanine 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 C 1 -C 4 alkyl-hydroxyl substituted (C 1 -C 4 alkyl-OH) group, a C 1 -C 4 alkoxyl group, a carboxylic acid group, a C 1 -C 4 alkyl nitrile-substituted (CONHC 1 -C 4 alkyl-CN) group, or C 1 -C 4 alkyl-substituted (CONHC 1 -C 4 alkyl) or C 1 -C 4 alk
  • a dipeptide derivative is provided.
  • the dipeptide derivative is represented by formula (I),
  • a dipeptide derivative is provided.
  • the dipeptide derivative is represented by formula (I),
  • a dipeptide derivative is provided.
  • the dipeptide derivative is represented by formula (I),
  • a method for treating a neutrophil inflammatory disorders with an antagonist of Formyl Peptide Receptor 1 includes providing a derivative of N—(N-aroyl-L-tryptophanyl)-D-phenylalanine methyl esters represented by formula (II), wherein:
  • R 1 is one selected from a group consisting of a hydrogen, a hydroxyl group and a methoxy group
  • R 2 is one selected from a group consisting of a non-substituted phenyl group, a mono-substituted phenyl group, a di-substituted phenyl group, or a tri-substituted phenyl group, a pyridinyl group and a C 4 -C 6 cycloalkyl group;
  • R 3 is one selected from a group consisting of a non-substituted benzoyl group, a mono-substituted benzoyl group, a di-substituted benzoyl group and a tri-substituted benzoyl group;
  • R 4 is one selected from a group consisting of a hydroxyl, a C1-C4 alkoxyl and a glycin-nitrile groups.
  • a method for treating a neutrophil inflammatory disorder with an antagonist of formyl peptide receptor 1 includes providing a derivative of N—(N-aroyl-L-tryptophanyl)-D-phenylalanine methyl esters represented by formula (II), wherein:
  • R 1 is one selected from a group consisting of a hydrogen, a hydroxyl group and a methoxy group
  • R 2 is one selected from a group consisting of a non-substituted phenyl group, a mono-substituted phenyl group, a di-substituted phenyl group, or a tri-substituted phenyl, a pyridinyl and a C 4 -C 6 cycloalkyl groups;
  • R 3 is one selected from a group consisting of a non-substituted benzoyl group, a mono-substituted benzoyl group, a di-substituted benzoyl group and a tri-substituted benzoyl group;
  • R 4 is one selected from a group consisting of a hydroxyl group, a C1-C4 alkoxyl group and a glycin-nitrile group.
  • a dipeptide derivative is provided.
  • the dipeptide derivative is represented by formula (II),
  • R 1 is selected from one of a hydrogen and a hydroxyl group
  • R 2 is one selected from a group consisting of non-substituted phenyl group, mono-substituted phenyl group, di-substituted phenyl group, or tri-substituted phenyl group and pyridinyl group;
  • R 3 is one selected from a group consisting of a non-substituted benzoyl group, a mono-substituted benzoyl group, a di-substituted benzoyl group and a tri-substituted benzoyl group;
  • R 4 is selected from one of C1-C4 alkoxyl group and a glycin-nitrile group.
  • FIGS. 1( a )- 1 ( b ) show the influences of HCH6-1 on releasing lactate dehydrogenase from human neutrophils
  • FIGS. 2( a )- 2 ( u ) show selective inhibition of HCH6-1 for fMLF-induced CD11b expression in human neutrophils
  • FIGS. 3( a )- 3 ( h ) show inhibition of HCH6-1 for the effect on FNLFNYK combined with FPR1 on the membranes of human neutrophils
  • FIGS. 4( a )- 4 ( d ) show the significant capability of HCH6-1 to suppress phosphorylation for MAPKs (ERK, p38 and INK), as well as Akt.
  • the excipient in the present invention also refers to a pharmaceutically acceptable carrier or excipient, or a bio-available carrier or excipient, including a solvent, dispersant, coat, antibacterial or antifungal agent, preservative or slow absorber, which is a proper compound used to prepare a formulation in the prior art.
  • a carrier or excipient does not have any activity for treatments itself.
  • the compound disclosed in the present invention cooperating with a pharmaceutically acceptable carrier or excipient is prepared as various formulations, and will not result in adverse drug reactions, allergies or other inappropriate responses after being administered to animals or humans.
  • the compound in the present invention, cooperating with a pharmaceutically acceptable carrier or excipient is for use in clinics and human.
  • Effective dose means a dose which is enough to improve or prevent medical symptoms or biological manifestation. Effective dose may be also stated as casting dose for use in diagnosis. Unless there is other description in the specification, “active compound” and “pharmaceutically active compound” are substitutes for each other and refer to a pharmaceutical, pharmacological or therapeutic substance as well as other effective material.
  • a dipeptide derivative containing a formula (I) is disclosed in the present invention.
  • the chiral centers in formula (I) are S and R configurations respectively.
  • RK and RT are respectively selected from one of the combination of hydrogen atom, hydroxyl group, C 1 -C 4 alkyl group substitute on hydroxyl group, C 1 -C 4 alkoxyl group, carboxylic acid group, C 1 -C 4 alkyl nitrile substitute, C 1 -C 4 alkyl substitute or C 1 -C 4 alkoxyl substitute on amide group, C 1 -C 4 alkyl substitute on the ester group or C 1 -C 4 alkyl group substitute on the aromatic ring of benzoyl group.
  • RM and RS are respectively selected from hydrogen atom, hydroxyl group, phenyl group, pyridinyl, carboxylic acid group, or C 1 -C 4 alkoxyl substitute on the ester group, or a hydroxyl group, halogen group, C 1 -C 4 alkoxyl group, C 1 -C 4 alkyl group substitute on the aromatic ring of benzoyl group.
  • the dipeptide derivatives are synthesized via one of the following Schemes 1-4.
  • Compounds 2-13, 16-24, 25-27 and 14-15 are synthesized by Schemes 1-4 respectively.
  • Each compound may be further classified into major or minor products and noted as ‘a’ or ‘b’ respectively.
  • R 1 -R 4 are represented as substitutions.
  • a pharmaceutically acceptable salt, solvate or combination thereof may be adopted for the dipeptide derivatives.
  • Scheme 1 is for the preparation of N—(N-aroyl-L-tryptophanyl)-D-phenylalanine methyl esters and their analogs, with which compounds 2-13 are synthesized.
  • Reagents and conditions (a) 2.0 N NaOH, aroyl chlorides, 20 h; (b) D-phenylalanine methyl ester, HBTU, DIEA, DCM, 6 h; (c) 2.0 N NaOH, benzoyl chloride, 20 h; and (d) D-phenylalaninol, HBTU, DIEA, DCM, 6 h.
  • Scheme 2 is for the preparation of N—(N-nictotinoyl-L-trypto-phanyl)-D-phenylalanine methyl esters, with which compounds 16-24 are synthesized.
  • Reagents and conditions (a) nicotinoyl chloride, pyridine, 20 h; (b) 1.0 M LiOH, THF, 1 h; and (c) D-phenylalanine methyl ester, HBTU, DIEA, DCM, 6 h.
  • Scheme 3 is for the synthesis of N—(N-benzoyl-L-tryptophanyl)-para-substituted-D-phenylalanine methyl esters and N—(N-benzoyl-L-tryptophanyl)-3-cyclohexyl-D-alanine methyl esters, with which compounds 25-27 are synthesized.
  • Scheme 4 is for the preparation of N—(N-benzoyl-L-tryptophanyl)-D-phenylalanine-glycine-nitriles, with which compounds 14-15 are synthesized.
  • Degranulation of azurophilic granules was determined by elastase release as described above. Experiments were performed using MeO-Suc-Ala-Ala-Pro-Val-p-nitroanilide as the elastase substrate. Briefly, after supplementation with MeO-Suc-Ala-Ala-Pro-Val-p-nitroanilide (100 ⁇ M), neutrophils (6 ⁇ 10 5 ml ⁇ 1 ) were equilibrated at 37° C. for 2 min and incubated with drugs for 5 min.
  • Cells were activated by 30 nM fMLP or 1.5 nM WKYMVm for 10 min with the pre-process of 0.5 ⁇ g ml ⁇ 1 CB for 3 min, and changes in absorbance at 405 nm were continuously monitored to evaluate elastase release. Results are expressed as the percentage of elastase release in the drug-free control group, DMSO.
  • Tables 1-6 demonstrate the inhibitory effects of dipeptide derivatives in the present invention on superoxide anion generation and elastase release by human neutrophils in response to specific activators of FPR1 or FPR2.
  • Table 1 demonstrates the inhibitory effects of N—(N-aroyl-L-tryptophanyl)-D-phenylalanine methyl esters and their analogs on O 2 •- generation and elastase release by human neutrophils in response to fMLP/CB.
  • Table 2 demonstrates the inhibitory effects of N—(N-benzoyl-L-tryptophanyl)-para-substituted-D-phenylalanine methyl esters and N—(N-benzoyl-L-tryptophanyl)-3-cyclohexyl-Dalanine methyl esters on O 2 •- generation and elastase release by human neutrophils in response to fMLP/CB.
  • Table 3 demonstrates the inhibitory effects of N—(N-benzoyl-L-tryptophanyl)-D-phenylalanine analogs/derivatives on O 2 •- generation and elastase release by human neutrophils in response to fMLP/CB.
  • Table 4 demonstrates respectively inhibitory the effects of compounds 3, 6, 24a, and 24b on O 2 •- generation and elastase release by human neutrophils in response to fMLP/CB and WKYMVm/CB.
  • Tables 5 and 6 explore whether there is an anti-inflamatory effect in the dipeptide derivatives. Because ferricytochrome c cannot penetrate cell membranes, it reacts with superoxide anion extracellularly. Also, there are absorptive reactions at 550 nm, and differences among the absorptive reactions can be used to evaluate the influence on the release of superoxide anion. The elastase is released by degranulation as the neutrophil is activated. Tables 5 and 6 use the substrate, MeO-Suc-Ala-Ala-Pro-Val-p-nitroanilide, with the specificity for reacting with the elastase so as to evaluate the influence of the candidate compound on the elastase release.
  • Table 5 demonstrates the comparison for each of compound 3 (HCH6-1), compound 6 (HCH30-2), compound 19a (HCH108-4), compound 19b (HCH108-3), compound 22a (HCH113-4), compound 22b (HCH113-3), compound 24a (HCH99-2), compound 24b (HCH99-1), compound 27a (HCH90-2-2) and compound 27b (HCH90-2-1) inhibiting superoxide anion generation of human neutrophils induced by specific activator of FPR1, fMLP and specific activator of FPR2, WKYMVm.
  • Table 6 demonstrates the comparison for each of compound 3 (HCH6-1), compound 6 (HCH30-2), compound 19a (HCH108-4), compound 19b (HCH108-3), compound 22a (HCH113-4), compound 22b (HCH113-3), compound 24a (HCH99-2), compound 24b (HCH99-1), compound 27a (HCH90-2-2) and compound 27b (HCH90-2-1) inhibiting elastase release of human neutrophils induced by specific activator of FPR1, fMLP and specific activator of FPR2, WKYMVm.
  • Embodiments 1-5 are preparing methods for the dipeptide derivatives in the present invention.
  • 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.
  • 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.
  • reaction mixture 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 methyl ester (1.0 mmole) and N-nicotinoyl-L-tryptophan 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 ethyl acetate to afford the products (compounds 15a and 15b).
  • TFA trifluroacetic acid
  • Embodiments 6-12 are applications of various activity tests for each dipeptide derivative, such as the evaluation of the inhibition of elastase release and superoxide anion generation induced by specific activators of FPR1, fMLP and specific activators of FPR2, formyl peptide receptor-like 1 agonist (WKYMVm), as well as other related studies on the pharmacological mechanism.
  • the methods and procedures for activity tests and the results are as follows.
  • FIGS. 1( a )- 1 ( b ) show the influences of HCH6-1 on releasing lactate dehydrogenase (LDH) from human neutrophils under the following experimental conditions.
  • the suspension of neutrophils was reacted with different concentrations of candidate compounds for 15 min, or fixed concentrations of candidate compounds for various times.
  • Total LDH total lactate dehydrogenase
  • FIG. 1( a ) shows that HCH6-1's inhibitory effects on fMLP-induced superoxide anion generation and elastase release of neutrophils were not the results of toxicity to the neutrophils.
  • FIG. 1( b ) shows that there was no significant toxicity for HCH6-1 (30 ⁇ M) treatment of the cells during a long period, such as 120 min, so as to demonstrate that high concentrations of HCH6-1 reacting with the cells for 120 min was non-toxic for the cells.
  • O 2 •- generation was based on the SOD-inhibitable reduction of ferricytochrome c.
  • neutrophils were equilibrated at 37° C. for 2 min and incubated with drugs for min.
  • the degranulation of azurophilic granules was determined by elastase release as described above. Experiments were performed using MeO-Suc-Ala-Ala-Pro-Val-p-nitroanilide as the elastase substrate. Briefly, after supplementation with MeO-Suc-Ala-Ala-Pro-Val-p-nitroanilide (100 ⁇ M), neutrophils (6 ⁇ 10 5 ml 1 ) were equilibrated at 37° C. for 2 min and incubated with drugs for 5 min.
  • Cells were activated by 30 nM fMLF or 1.5 nM WKYMVm for 10 min in the pre-process of 0.5 ⁇ g ml ⁇ 1 CB for 3 min, and changes in absorbance at 405 nm were continuously monitored to assay the elastase release. The results are expressed as the percentage of elastase release in the drug-free control group.
  • the suspension of neutrophils was mixed at 37° C. and pre-heated for 5 min, and then compounds with different concentrations for measurements were added. After that, CB with 1 ⁇ g ml ⁇ 1 was added to react for 3 min, and subsequently fMLF with 30 nM is added to react for 10 min. And the reaction termination is done by on-ice setting. The supernatant was removed after centrifugation, and make the cells suspension again in the balanced salt solution containing bovine serum albumin (BSA). Anti-CD11b with fluorescein isothiocyanate (FITC) labeling was added, and kept on ice and in the dark. Finally, a balanced salt solution was added to terminate the reaction.
  • BSA bovine serum albumin
  • FITC fluorescein isothiocyanate
  • Membranes of human neutrophils contain fMLF receptor, formyl peptide receptor 1 (FPR1), with which formyl-NIe-Leu-Phe-NIe-Tyr-Lys (FNLFNYK) carrying the fluorescence property was combined with FPR1 and competed with the candidate compound for receptor binding. Therefore, by binding with the receptor, it was possible to further clarify whether the compound interacts with the receptor.
  • FIGS. 3( a )- 3 ( h ) showed the inhibition of HCH6-1 regarding the effect of FNLFNYK combined with FPR1 on the membranes of human neutrophils.
  • the experimental results showed that the HCH6-1 concentration was correlated to the inhibition of FNLFNYK bound to FPR1, while IC 50 was 2.02 ⁇ 0.34 ⁇ M.
  • MAPKs Mitogen-activated protein kinases
  • Akt phosphorylation are closely related to the regulation of cell inflammatory response. By specific binding of antibodies, each compound's influence on protein expression activated by different signals was observed.
  • MAPKs ERK, p38, and INK
  • Akt signal transduction pathways are involved in the regulation of superoxide anion generation and elastase release. It is can be seen from the above-mentioned experiments that HCH6-1 is capable of competitively inhibiting superoxide anion generation and elastase release. Whether downstream MAPKs and Akt signal transduction pathways of FPR1 were involved in the regulation of superoxide anion generation and elastase release is explored below.
  • FIGS. 4( a )- 4 ( d ) showed the capability of HCH6-1 to significantly inhibit phosphorylation for MAPKs (ERK, p38 and INK) and Akt.
  • the experimental conditions were as follows. HCH6-1 (10 ⁇ M) was pre-processed for 5 min, followed by stimulus of fMLF (3-30 nM) for 30 sec. The experimental results showed that HCH6-1 inhibited signal transductions of MAPKs and Akt in cells. With a low concentration stimulus of fMLF (3 nM), HCH6-1 significantly suppressed phosphorylation for MAPKs and Akt, and thus an indirect proof for the competitive capability is provided, as shown in FIGS. 4( a )- 4 ( d ).
  • Results are expressed as the mean ⁇ SEM. Data were analyzed using GraphPad Prism software (GraphPad Software, San Diego, Calif.). Statistical analysis was performed using a Student's t-test or one-way analysis of variance (ANOVA), followed by a Tukey range test. A value of p ⁇ 0.05 was considered statistically significant.
  • the present invention utilizes simple synthesizing methods to generate a series of dipeptide derivatives, in which two amino acids need to be L (5) and D (R) configurations respectively, and the N-terminal and C-terminal are substituted. It was found that this series of compounds excellently suppresses superoxide anion generation and elastase release of human neutrophils in the experimental mode which were induced by specific activators of FPR1, fMLF. Although superoxide anion generation and elastase release of human neutrophils induced by specific activators of FPR2, WKYMVm were also suppressed, there was a significant decrement by 3-20 fold compared to the inhibition induced by specific activators of FPR1. It is shown that this novel series of peptide derivatives selectively antagonizes against FPR1.
  • compound 3 (HCH6-1) has only slight influence whenever it is triggered by non-FPR1 activation.
  • compound 3 (HCH6-1) competitively inhibited the downstream signal transduction pathways of FPR1, including calcium, MAPKs and Akt.
  • HCH6-1 selectively and competitively inhibits FPR1 to activate human neutrophils.
  • HCH6-1 is capable of inhibiting the combination of N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein, one kind of FPR-like fluorescein derivative, with FPR1.
  • compound 3 (HCH6-1) is capable of competitively inhibiting FPR1.
  • R 1 is one selected from a group consisting of a hydrogen, a hydroxyl group and a methoxy group
  • R 2 is one selected from a group consisting of a non-substituted phenyl group, a mono-substituted phenyl group, a di-substituted phenyl group, or a tri-substituted phenyl group, a pyridinyl group and a C 4 -C 6 cycloalkyl group;
  • R 3 is one selected from a group consisting of a non-substituted benzoyl group, a mono-substituted benzoyl group, a di-substituted benzoyl group and a tri-substituted benzoyl group;
  • R 4 is one selected from a group consisting of a hydroxyl, a C1-C4 alkoxyl and a glycin-nitrile groups.
  • R 1 is one selected from a group consisting of a hydrogen, a hydroxyl group and a methoxy group
  • R 2 is one selected from a group consisting of a non-substituted phenyl group, a mono-substituted phenyl group, a di-substituted phenyl group, or a tri-substituted phenyl, a pyridinyl and a C 4 -C 6 cycloalkyl groups;
  • R 3 is one selected from a group consisting of a non-substituted benzoyl group, a mono-substituted benzoyl group, a di-substituted benzoyl group and a tri-substituted benzoyl group;
  • R 4 is one selected from a group consisting of a hydroxyl group, a C1-C4 alkoxyl group and a glycin-nitrile group.
  • R 1 is selected from one of a hydrogen and a hydroxyl group
  • R 2 is one selected from a group consisting of non-substituted phenyl group, mono-substituted phenyl group, di-substituted phenyl group, or tri-substituted phenyl group and pyridinyl group;
  • R 3 is one selected from a group consisting of a non-substituted benzoyl group, a mono-substituted benzoyl group, a di-substituted benzoyl group and a tri-substituted benzoyl group;
  • R 4 is selected from one of C1-C4 alkoxyl group and a glycin-nitrile group.

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