Cat. No.: HY-184654

MR-39

MR-39 is a FPR2 agonist (EC₅₀ = 3.9 μM). MR-39 activates FPR2 to promote neuroinflammation resolution (downregulates IL-1β and TNF-α, modulates NF-κB), upregulates synaptic proteins (synaptic proteins) and improves dendritic spine morphology. MR-39 inhibits MAPK/ERK and AKT phosphorylation in glioblastoma, induces S-phase arrest, and suppresses migration, angiogenesis, and hypoxic adaptation. MR-39 reduces Aβ plaque burden via inhibiting MyD88/NF-κB and NLRP3 inflammasome. MR-39 can be used for research on autism spectrum disorder, Alzheimer's disease, and glioblastoma.

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CAS No.: 2169267-60-9
Formule: C₂₇H₂₃ClF₂N₄O₂
Masse moléculaire:508.95

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Please store the product under the recommended conditions in the Certificate of Analysis.

MR-39 Chemical Structure

CAS No.: 2169267-60-9

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Activité biologique
- Description
- IC₅₀ & Target
- Cellular Effect
- In Vitro
- Parmacokinetics
- In Vivo
Chemical Information
Pureté et documentation
Références
Calculators
Help & FAQs
Classifications
Bioz

Activité biologique

Description

IC₅₀ & Target^[1]^[2]^[3]^[4]

HIF-1α

Caspase-1

IL-10

IL-4

IL-1β

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Cellular Effect

Cell Line	Type	Value	Description	References
U-87MG ATCC	IC50	12.56 μM	Dose-dependent antiproliferative activity against U87-MG cells. Dose-dependent antiproliferative activity against U87-MG cells.	41652630
U138-MG	IC50	12.82 μM	Dose-dependent antiproliferative activity against U138-MG cells Dose-dependent antiproliferative activity against U138-MG cells	41652630
U-251	IC50	9.75 μM	Dose-dependent antiproliferative activity against U251-MG cells Dose-dependent antiproliferative activity against U251-MG cells	41652630

In Vitro

MR-39 (10 μM) shows low-to-moderate interactions with cannabinoid CB1/CB2 receptors (55% displacement), DAT (87% displacement), 5-HT₂B receptor (59% displacement), and L-type calcium channel (84% displacement) in the Mini Safety 44 Panel, while showing no significant interaction with the remaining targets^[1].
MR-39 (0.1-10 μM) inhibits hERG (IC₅₀= 1.98 μM), hNav1.5 (IC₅₀= 4.74 μM), and hCav1.2 (IC₅₀= 0.68 μM) ion channels in HEK-293 cells, suggesting potential cardiotoxicity risk^[1].
MR-39 (0.04-100 μM; 72 h) exhibits cytotoxicity in HepG2 cells with an AC₅₀ of 0.625 μM, indicating low-to-moderate hepatotoxicity^[1].
MR-39 (7.81-250 μg/mL; 90 min exposure, followed by 48 h culture) shows no genotoxicity in Salmonella TA98 and TA100 strains (Ames test)^[1].
MR-39 is stable in plasma (t_1/2 = 371, 932, and 1200 min in mouse, monkey, and human, respectively), shows a t_1/2 of 64 min in human liver microsomes, but is metabolized rapidly in hepatocytes (t_1/2 = 12.7, 14.8, and 26.6 min in mouse, monkey, and human, respectively), suggesting that non-CYP pathways may predominate; it exhibits high plasma protein binding (>92%) and blood-to-plasma ratios of 0.776, 0.906, 0.628, and 0.739 in mouse, rat, dog, and human, respectively, indicating that it distributes mainly in plasma^[1]. MR-39 (3 μM; 60 min) shows moderate permeability in Caco-2 cell monolayers, with P_app AB (apical-to-basal) of 0.669×10^-6 cm/s and P_app BA (basal-to-apical) of 8.2×10^-6 cm/s, and an efflux ratio (ER) of 12.3, indicating significant efflux activity; in the presence of the P-gp inhibitor Verapamil (HY-14275), AB increases to 2.42, BA decreases to 5.29, and ER drops to 2.19; in the presence of the BCRP inhibitor Fumitremorgin C (HY-N2143), AB increases to 1.91, BA decreases to 9.19, and ER drops to 4.81. These results indicate that MR-39 interacts with both P-gp and BCRP, with a stronger interaction with P-gp than with BCRP^[1].
The antiproliferative effects of MR-39 on glioblastoma cells and its neuroprotective effects against Aβ_1-42-induced neuroinflammation in hippocampal organotypic cultures are both blocked by the FPR2 antagonist WRW4 (HY-P1119) and are absent in FPR2 knockout cultures, indicating that its effects are FPR2-dependent^[2]^[4].
MR-39 (5-100 μM; 48 h) shows dose-dependent antiproliferative activity against human glioblastoma cells, with IC₅₀values of 12.56 μM (U87-MG), 12.82 μM (U138-MG), and 9.75 μM (U251-MG)^[2].
MR-39 (10 μM; 48 h) reduces Ki67 expression, inhibits MAPK/ERK and AKT phosphorylation, and induces non-canonical p53-dependent S-phase arrest (with CCND2 mRNA upregulation, CDK1 mRNA downregulation, p53 protein upregulation, and p27 protein downregulation, while p21 remains unchanged) in U87-MG and U138-MG cells^[2].
MR-39 (10 μM; 48 h) downregulates gene pathways related to migration/invasion, angiogenesis, and hypoxia response in U87-MG cells, as shown by RNA-seq and RT-qPCR^[2].
MR-39 (10 μM; 48 h) upregulates E-cadherin and downregulates N-cadherin, Slug, Snail, MMP-2, FN1, CPA4, VEGF, and VE-cadherin mRNA expression in U87-MG and U138-MG cells, and reduces FN1 and VEGF protein levels in U87-MG cells^[2].
MR-39 (10 μM; 24-72 h) inhibits cell migration (approximately 20% inhibition) in U138-MG and U251-MG cells as shown by wound healing assay^[2].
MR-39 (10 μM; 48 h) inhibits in vitro angiogenesis (reducing loop formation, loop area, and loop perimeter by approximately 50%) in EA.hy926 endothelial cells^[2].
MR-39 (10 μM; 48 h) significantly reduces HIF-1α mRNA and protein expression under CoCl₂-induced chemical hypoxia and enhances the antiproliferative effect in U87-MG cells^[2].
MR-39 reduces NF-κB protein levels in glioblastoma cells and inhibits NF-κB phosphorylation in hippocampal organotypic cultures, indicating that it regulates the NF-κB inflammatory signaling pathway^[2]^[4].
MR-39 downregulates pro-inflammatory cytokines IL-1β and TNF-α expression in both U87-MG and U138-MG glioblastoma cells and in WT mouse hippocampal organotypic cultures^[2]^[4].
MR-39 (10 μM; 48 h) downregulates pro-inflammatory genes COX-2, CXCL-7, NFKB1, and IL-6 mRNA expression in U87-MG and U138-MG cells^[2].
MR-39 (1 μM; pretreated for 1 h, followed by 24 h stimulation) inhibits Aβ_1-42-induced MyD88 synthesis, NF-κB phosphorylation, and increases in NLRP3, Caspase-1, and ASC protein levels via an FPR2-dependent mechanism in WT mouse hippocampal organotypic cultures^[4].
MR-39 (1 μM; pretreated for 1 h, followed by 24 h stimulation) reduces Aβ_1-42-induced LDH release, increases anti-inflammatory IL-4 release (but decreases IL-10 levels; Aβ_1-42 alone has no effect on IL-10 in WT cultures), and shows no significant effect on NO release via an FPR2-dependent mechanism in WT mouse hippocampal organotypic cultures^[4].
MR-39 (10 μM; 4 h and 72 h) significantly stimulates neurite elongation in primary hippocampal neurons from BTBR mice, restoring neurite length to B6 control levels, while showing no significant effect on hippocampal neurons from B6 mice^[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Cytotoxicity Assay^[1]

Cell Line:

HepG2 cells
Concentration:

0.04, 0.1, 0.4, 1, 4, 10, 40 and 100 μM
Incubation Time:

72 h
Result:

Showed cytotoxic effects with an AC₅₀ of 0.625 μM, indicating low to moderate hepatotoxicity.

Cell Proliferation Assay^[2]

Cell Line:

U87-MG, U138-MG, U251-MG cells
Concentration:

5, 7.5, 10, 25, 50 and 100 μM (dose-response); 10 µM (subsequent experiments)
Incubation Time:

48 h
Result:

Showed dose-dependent antiproliferative activity in all three cell lines, with IC₅₀values of 12.56 µM (U87-MG), 12.82 µM (U138-MG), and 9.75 µM (U251-MG). The effect was reversed by the FPR2 antagonist WRW4 (10 µM) and by FPR2 siRNA silencing.

Cell Cytotoxicity Assay^[2]

Cell Line:

U87-MG, U138-MG, U251-MG cells
Concentration:

10 µM
Incubation Time:

48 h
Result:

Showed no decrease in cell viability, indicating that the antiproliferative effect was cytostatic rather than cytotoxic.

Western Blot Analysis^[2]

Cell Line:

U87-MG cells
Concentration:

10 µM
Incubation Time:

48 h
Result:

Reduced ERK1/2 phosphorylation by approximately 70% and AKT phosphorylation by approximately 50%. Decreased FN1, VEGF, and NF-κB protein levels. Increased p53 protein levels, decreased p27 protein levels, while p21 protein levels remained unchanged.

Cell Cycle Analysis^[2]

Cell Line:

U87-MG, U138-MG cells
Concentration:

10 µM
Incubation Time:

48 h
Result:

Induced S-phase accumulation and reduced G2/M-phase population. The effect was reversed by WRW4 (10 µM) co-treatment.

Immunofluorescence^[2]

Cell Line:

U87-MG, U138-MG cells
Concentration:

10 µM
Incubation Time:

48 h
Result:

Significantly reduced Ki67 expression in both cell lines, confirming decreased cell proliferation.

Immunofluorescence^[2]

Cell Line:

U87-MG cells
Concentration:

10 µM (with 100 µM CoCl₂ for hypoxia induction)
Incubation Time:

48 h
Result:

Under CoCl₂-induced hypoxic conditions, reduced HIF-1α protein expression, while showing no effect on HIF-1α under normoxic conditions.

RT-PCR^[2]

Cell Line:

U87-MG, U138-MG cells
Concentration:

10 µM
Incubation Time:

48 h
Result:

Increased CCND2 mRNA and decreased CDK1 mRNA levels. Upregulated E-cadherin; downregulated N-cadherin, Slug, Snail, MMP-2, FN1, CPA4, VEGF, and VE-cadherin mRNA levels. Downregulated HIF-1α mRNA under hypoxic conditions. Downregulated COX-2, CXCL-7, NFKB1, IL-1β, and IL-6 mRNA levels. Similar trends were observed in U138-MG cells.

Cell Migration Assay ^[2]

Cell Line:

U138-MG, U251-MG cells
Concentration:

10 µM
Incubation Time:

Monitored at 0, 24, 48, and 72 h
Result:

Significantly inhibited gap closure by approximately 20%, an effect reversed by WRW4 (10 µM) co-treatment. Similar results were obtained in U251-MG cells.

Cell Cytotoxicity Assay^[4]

Cell Line:

WT and FPR2 KO mouse hippocampal organotypic cultures
Concentration:

1 µM (MR-39); 10 µM (fibrillar Aβ_1-42)
Incubation Time:

Pretreated with MR-39 for 1 h, followed by co-stimulation with Aβ_1-42 for 24 h
Result:

Reduced Aβ_1-42-induced LDH release in WT cultures, while showing no effect in FPR2 KO cultures. The effect was blocked by the FPR2 antagonist WRW4 (10 µM).

ELISA Assay^[4]

Cell Line:

WT and FPR2 KO mouse hippocampal organotypic cultures
Concentration:

1 µM (MR-39); 10 µM (fibrillar Aβ_1-42); 10 µM (WRW4)
Incubation Time:

Pretreated with MR-39 for 1 h, followed by co-stimulation with Aβ_1-42 for 24 h
Result:

Decreased pro-inflammatory cytokines IL-1β and TNF-α levels in WT cultures (but showed no effect on IL-6). Increased anti-inflammatory IL-4 release but decreased IL-10 levels in WT cultures. Inhibited MyD88 synthesis, NF-κB phosphorylation, and NLRP3, Caspase-1, and ASC protein levels in WT cultures. All effects were blocked by WRW4 and absent in FPR2 KO cultures.

Parmacokinetics

Species	Dose	Route	T_max	C_max
Mice^[1]	10 mg/kg	i.p.	1 h	813 ng/mL

In Vivo

MR-39 (10 mg/kg; i.p.; once daily; for 8 days) shows anti-inflammatory and synaptic protective effects in BTBR mice, including reduction of inflammatory cytokines, modulation of NF-κB signaling, upregulation of synaptic proteins, and amelioration of dendritic spine morphological abnormalities^[1].
MR-39 (10 mg/kg; i.p.; once daily; for 14 consecutive days) shows favorable in vivo safety in C57BL/6NCRL mice, with no drug accumulation or treatment-related toxicity observed^[1].
MR-39 (10 mg/kg; i.p.; once daily; for 8 days) restores hippocampal LXA4 levels, upregulates FPR2 mRNA expression (with protein levels also upregulated in BTBR mice), reduces pro-inflammatory Tnf-α and Il-1β mRNA levels, increases anti-inflammatory IL-10 mRNA levels, and significantly improves social behavior and reduces self-grooming in both BTBR and VPA mouse models of ASD^[3].
MR-39 (10 mg/kg; i.p.; twice a week; for 20 weeks) improves cortical neuronal survival, reduces cortical microglial density and hippocampal Aβ plaque area, but shows no significant effects on hippocampal neurons, hippocampal microglia, or astrocytes in APP/PS1 mouse models^[4].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model:

3-month-old male BTBR T+ tf/J mice^[1]^[3].
Dosage:

10 mg/kg
Administration:

Intraperitoneal injection (i.p.), once daily for 8 consecutive days
Result:

Significantly reduced IL-1β and TNF-α mRNA levels in both hippocampus and cortex. Did not restore NF-κB mRNA levels in either region, but rescued decreased NF-κB protein in the hippocampus and increased it in the cortex, as measured by qPCR and Western blot.
Restored decreased hippocampal LXA4 levels to B6 levels. Significantly increased FPR2 mRNA and protein expression in the hippocampus, as determined by ELISA, RT-qPCR, and Western blot.
Decreased synaptophysin mRNA levels but significantly upregulated its protein levels in both hippocampus and cortex. Restored SYNPO mRNA and protein in the hippocampus.
Showed no effect on VAMP-2 mRNA or on PSD95 and synaptotagmin protein levels in either brain region.
In ex vivo cortical slices, selectively modulated spine morphology without altering spine density. Increased mushroom spine density and thin spine length in B6 mice, while reducing thin spine length and mushroom spine head diameter in BTBR mice, normalizing these features toward B6 levels.
In the three-chambered social test, significantly increased the time spent in the chamber with the novel mouse compared to the novel object, indicating improved sociability.
In the reciprocal social interaction test, significantly increased the number of following, push-crawl, nose-to-nose, and nose-to-anogenital sniffing bouts compared to BTBR-vehicle group.
Significantly decreased self-grooming behavior during social interaction, but did not rescue self-grooming when the mouse was alone in the cage, suggesting the effect depends on social context.

Animal Model:

Male C57BL/6NCRL mice^[1].
Dosage:

10 mg/kg
Administration:

Intraperitoneal injection (i.p.), once daily for 14 consecutive days
Result:

Showed no clinical signs attributable to treatment-related toxicity throughout the study.
Body weight gains remained within the normal physiological range for age- and strain-matched mice.
Plasma and brain concentrations at 24 h after the last dose were both below LOQ, indicating no significant tissue accumulation.

Animal Model:

Pregnant mice received a single intraperitoneal injection of valproic acid (VPA) at 500 mg/kg on gestational day 12.5 (GD 12.5), and 3-month-old male offspring were used for the experiment^[3].
Dosage:

10 mg/kg
Administration:

Intraperitoneal injection (i.p.), once daily for 8 consecutive days
Result:

Significantly increased the decreased hippocampal LXA4 level in VPA mice, as measured by ELISA.
Significantly increased hippocampal FPR2 mRNA expression, but did not significantly change FPR2 protein expression.
Significantly reduced hippocampal mRNA levels of pro-inflammatory cytokines Tnf-αand Il-1β.
Significantly increased hippocampal mRNA levels of anti-inflammatory cytokine IL-10.
In the three-chambered social test, significantly increased the time spent in the chamber with the novel mouse compared to the chamber with the novel object, indicating improved sociability.
In the reciprocal social interaction test, significantly increased the number of following and nose-to-nose sniffing bouts, and significantly decreased the time spent in self-grooming compared to VPA-vehicle group.
As for BTBR mice, the self-grooming behavior was only reduced during social interaction, not when the mouse was alone, confirming that social context is critical for the MR-39 rescuing effect on stereotyped behavior.

Animal Model:

8-week-old male APP/PS1 double-transgenic mice co-expressing the human APP Swedish mutation and the human PS1 exon 9 deletion mutation. WT n = 12, WT + MR39 n = 5, APP/PS1 n = 10, APP/PS1 + MR39 n = 6^[4].
Dosage:

10 mg/kg
Administration:

Intraperitoneal injection (i.p.), twice a week for 20 consecutive weeks (from 8 weeks to 29 weeks of age)
Result:

Improved neuronal survival in the cortex (layer V) of APP/PS1 mice as shown by increased NeuN⁺ cell density.
Significantly reduced microglial cell density in the cortex of APP/PS1 mice, but showed no significant effect on microglial density in the hippocampus.
Showed no effect on astrocyte reactivity (GFAP⁺ staining) in the hippocampus of APP/PS1 mice.
Significantly reduced total Aβ plaque area in the hippocampus of APP/PS1 mice.
Showed no significant effect on the average number of Aβ plaques per area.
Showed no significant effect on the number of plaques across any size category.

Chemical Information

CAS No. 2169267-60-9
Masse moléculaire 508.95
Formule C₂₇H₂₃ClF₂N₄O₂
SMILES

FC1=CC=C(NC(N[C@@H](CC2=CC=C(C#N)C=C2)C(NCC3(CC3)C4=CC(Cl)=C(F)C=C4)=O)=O)C=C1
Livraison

Room temperature in continental US; may vary elsewhere.
Stockage

Please store the product under the recommended conditions in the Certificate of Analysis.

Pureté et documentation

Instruction de manipulation (2659 KB)

Références

[1]. Vitone, et al. Toward a Therapy for Autism Spectrum Disorder: The Formyl Peptide Receptor 2 Agonist MR-39 Supports Synaptic Health in the BTBR Mouse and Features a Favorable Safety Profile. ACS Pharmacology & Translational Science. 2026 June 24.

[2]. Ferraro MG, et al. Formyl peptide receptor 2 activation by MR-39 inhibits glioblastoma cell proliferation and invasiveness through suppression of multiple oncogenic pathways. J Transl Med. 2026 Feb 6;24(1):342. [Content Brief]

[3]. Cristiano C, et al. Behavioral, Anti-Inflammatory, and Neuroprotective Effects of a Novel FPR2 Agonist in Two Mouse Models of Autism. Pharmaceuticals (Basel). 2022 Jan 28;15(2):161. [Content Brief]

[4]. Trojan E, et al. The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Improves Ex Vivo and In Vivo Amyloid Beta (1-42)-Induced Neuroinflammation in Mouse Models of Alzheimer's Disease. Mol Neurobiol. 2021 Dec;58(12):6203-6221. [Content Brief]

[5]. Stama ML, et al. Novel ureidopropanamide based N-formyl peptide receptor 2 (FPR2) agonists with potential application for central nervous system disorders characterized by neuroinflammation. Eur J Med Chem. 2017 Dec 1;141:703-720.

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MR-39

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Chemical Information

Pureté et documentation

Références

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Help & FAQs

MR-39 Related Classifications

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