Emlenoflast (MCC7840) is a potent and selective small-molecule inhibitor of the NLRP3 inflammasome. It binds directly to the NACHT domain of NLRP3, blocking ATP hydrolysis and preventing inflammasome assembly. This inhibits the activation of caspase-1 and the subsequent maturation and secretion of pro-inflammatory cytokines IL-1β and IL-18, as well as pyroptotic cell death. [3]
In primary mouse microglia stimulated with LPS/ATP, MCC7840 inhibited IL-1β secretion with an IC50 of 4.7 nM. [3]
In human monocyte-derived macrophages (HMDM) stimulated with LPS/ATP, MCC7840 inhibited IL-1β secretion with an IC50 of 3.4 nM. [3]
In human monocyte-derived microglia (MDMi) stimulated with LPS/ATP, MCC7840 inhibited IL-1β secretion with an IC50 of 3.9 nM. [3]
In LPS-primed human THP-1 macrophages stimulated with ATP, MCC7840 inhibited IL-1β secretion with potency equivalent to MCC950. [3]
Off-target screening confirmed that MCC7840 was inactive at closely related inflammasomes (NLRP1, NLRC4, AIM2) and devoid of activity in a broad panel of binding, enzyme, kinase, and cell-based assays. [3]

Emlenoflast sodium is an MCC950 analog that functions well in blocking the activation of the NLRP3 inflammasome with IC50 <100 nM [1].

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MCC7840 potently inhibits NLRP3 inflammasome activation in human and mouse myeloid cells. In LPS-primed human THP-1 macrophages stimulated with ATP, MCC7840 ablated IL-1β secretion with potency equivalent to MCC950. [3]
In primary mouse microglia primed with LPS (200 ng/ml, 3 h) and stimulated with ATP (5 mM, 1 h), MCC7840 inhibited IL-1β secretion with an IC50 of 4.7 nM. [3]
In human monocyte-derived macrophages (HMDM) and monocyte-derived microglia (MDMi) primed with LPS and stimulated with ATP, MCC7840 inhibited IL-1β secretion with IC50 values of 3.4 nM and 3.9 nM, respectively. [3]
A radiolabelled competition assay demonstrated that MCC7840 and MCC950 interact at the same binding site on NLRP3, as MCC950 dose-dependently displaced ³H-MCC7840 binding to HEK cell membranes expressing human NLRP3. [3]
MCC7840 showed no activity against other inflammasomes (NLRP1, NLRC4, AIM2) and was inactive in a broad panel of safety screens (binding, enzyme, kinase, and cell-based assays). [3]

Emlenoflastodium (4 mg/kg; iv) exhibits half-life (3.39 h), AUC0-last (107097 ng?h/mL), and CL (0.621 mL/min/kg) in mice [2]. 20 mg/kg; po) demonstrated good oral bioavailability (67.2%), Cmax (60467 ng/mL) and half-life (5.02 h) in mice [2].

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In a murine NLRP3 gain-of-function model of Muckle-Wells syndrome (MWS; Nlrp3^A350V/- LysMcre mice), MCC7840 administered orally every second day from postnatal day 4 (P4) at a dose of 3 mg/kg provided complete protection from mortality, whereas MCC950 at the same dose showed significantly reduced survival. Body weight trajectories mirrored survival outcomes. This demonstrates that MCC7840 is more potent than MCC950 in vivo. [3]
In the unilateral 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease, daily oral gavage of MCC7840 (1, 3, or 10 mg/kg) starting 1 day before lesioning significantly reduced amphetamine-induced ipsilateral rotations (motor impairment) and preserved striatal dopamine, DOPAC, and HVA levels at all doses tested. Maximal efficacy was observed at 3 and 10 mg/kg. The ED50 for motor behavior was approximately 0.9 mg/kg, and for dopamine loss approximately 2.2 mg/kg. [3]
In the 6-OHDA model, chronic administration of MCC7840 via drinking water (0.3 mg/ml) starting 1 day before lesioning and continuing until study end (28 days) significantly attenuated neuroinflammation (as measured by ¹⁸F-DPA-714 PET), preserved dopamine transporter availability (¹⁸F-FBCTT PET), preserved dopamine uptake (¹⁸F-FDOPA PET), and prevented blood-brain barrier leakage (gadolinium-enhanced MRI). Plasma IL-1β levels were also suppressed, confirming target engagement. [3]
In the preformed α-synuclein fibril (PFF-Syn) mouse model of Parkinson's disease, MCC7840 administered via drinking water (0.3 mg/ml) either prophylactically (starting 1 day before PFF-Syn injection) or therapeutically (starting 4 months after PFF-Syn injection, after motor symptoms had emerged) both significantly improved motor function (rotarod and balance beam tests) at 6, 8, and 10 months post-injection. At 12 months, PET imaging with ¹⁸F-DPA-714 showed significantly reduced neuroinflammation in both treatment groups, which correlated with reduced microgliosis (Iba1 staining) and astrogliosis (GFAP staining). Striatal dopamine levels were preserved, and plasma IL-1β was suppressed (fully in the prophylactic group and by ~70% in the therapeutic group). [3]

A radiolabelled competition binding assay was performed to confirm that MCC7840 and MCC950 bind to the same site on NLRP3. Membranes from HEK cells expressing human NLRP3 were incubated with ³H-labelled MCC7840 and increasing concentrations of unlabelled MCC950. MCC950 dose-dependently displaced ³H-MCC7840 binding, indicating competitive interaction at the same binding site. [3]

THP-1 cell assay: Human THP-1 monocytes were differentiated into macrophage-like cells with PMA (0.5 μM, 3 h). Cells were then primed with ultrapure LPS (200 ng/ml, 3 h), washed, and pre-treated with varying concentrations of MCC7840 or MCC950 for 30 min, followed by stimulation with ATP (5 mM, 1 h) to activate the NLRP3 inflammasome. Supernatants were collected, and IL-1β levels were measured by ELISA. [3]
Primary mouse microglia assay: Microglia were isolated from postnatal day 0-1 C57BL/6J mouse brains using a column-free magnetic separation method. Cells were plated, primed with LPS (200 ng/ml, 3 h), pre-treated with MCC7840 for 30 min, and stimulated with ATP (5 mM, 1 h). IL-1β in supernatants was quantified by ELISA. IC50 values were calculated from dose-response curves. [3]
Human monocyte-derived macrophages (HMDM) and microglia (MDMi) assays: CD14+ monocytes were isolated from human buffy coats and differentiated into HMDM or MDMi using established protocols. Cells were primed with LPS, pre-treated with MCC7840, stimulated with ATP, and IL-1β secretion was measured by ELISA. [3]
Off-target screening: MCC7840 was tested in a broad panel of binding, enzyme, kinase, and cell-based assays to assess selectivity. It showed no significant activity against other inflammasomes (NLRP1, NLRC4, AIM2) and no off-target effects in the panel. [3]

Animal/Disease Models: Male C57BL/6 mice (7-9 weeks) [2]
Doses: 4 mg/kg intravenously (iv) (iv)(iv), 20 mg/kg orally (pharmacokinetic/PK/PK analysis)
Route of Administration: single intravenous (iv) (iv)bolus or oral Results of intragastric (po) (po)
Route of Administration: IV: t1/2=3.39 h; AUC0-last=107097 ng·h/mL; CL=0.621 ml/min/kg. Po: F=67.2%; Cmax=60467ng/ml; t1/2=5.02 hrs (hrs (hours)).

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Muckle-Wells syndrome (MWS) model: Nlrp3^A350V/- LysMcre mice (both sexes) were used. MCC7840 or MCC950 was administered orally by gavage every second day from postnatal day 4 (P4) until P22 at doses ranging from 0.03 to 30 mg/kg (for dose-response) or at a fixed dose of 3 mg/kg (for comparative study). Body weight and survival were monitored daily. [3]
6-OHDA Parkinson's disease model: Male C57BL/6J mice (8-12 weeks old) received a unilateral stereotaxic injection of 6-OHDA (12 μg in 2 μl saline with 0.2% ascorbic acid) or saline into the right dorsal striatum. MCC7840 was administered either by daily oral gavage (1, 3, or 10 mg/kg, in vehicle) starting 1 day before surgery and continuing until study termination (Day 28), or via drinking water (0.3 mg/ml) ad libitum starting 1 day before surgery and continuing throughout the study. Behavioural tests (amphetamine-induced rotations) were performed on Days 17 or 21. PET/MRI imaging was conducted on Days 24-28. At study end, brains were collected for dopamine quantification by LC-MS/MS, and plasma was collected for IL-1β ELISA. [3]
PFF-Syn Parkinson's disease model: Male C57BL/6J mice (8-12 weeks old) received a unilateral stereotaxic injection of preformed α-synuclein fibrils (PFF-Syn; 8 μg in 2 μl PBS) or PBS into the right dorsal striatum. MCC7840 was administered via drinking water (0.3 mg/ml) ad libitum either prophylactically (starting 1 day before PFF-Syn injection) or therapeutically (starting 4 months after PFF-Syn injection). Motor behaviour (rotarod and balance beam) was assessed at 4, 6, 8, and 10 months post-injection. PET/MRI imaging with ¹⁸F-DPA-714 was performed at 11-12 months. At study end (12 months), brains were collected for immunohistochemistry (Iba1, GFAP), autoradiography, and dopamine quantification; plasma was collected for IL-1β ELISA. [3]

Following a single oral dose (20 mg/kg) in fasted male C57BL/6J mice, MCC7840 demonstrated superior pharmacokinetic properties compared to MCC950: higher Cmax, higher AUC, and an extended half-life (5.0 h for MCC7840 vs. 2.4 h for MCC950). Oral bioavailability was 68% for MCC7840 and 71% for MCC950. [3]
After oral dosing (20 mg/kg), MCC7840 achieved significantly higher total brain concentrations than MCC950 at 2 h post-dose (approximately 4-fold higher). The plasma-to-brain ratio was ~3.5%. Brain concentrations remained well above the IC50 for NLRP3 inhibition (4.7 nM) for at least 24 h. [3]
When administered via drinking water (0.3 mg/ml) ad libitum for 5 days, MCC7840 achieved consistent steady-state levels in plasma, brain, and CSF, with concentrations exceeding the microglial IC50 and IC90 values throughout the 24 h period. CSF concentrations matched those in brain tissue, confirming CNS exposure. [3]
Intravenous administration (4 mg/kg) in mice showed low clearance and low volume of distribution for MCC7840, attributed to high plasma protein binding (>99%). [3]
Oral pharmacokinetics were also assessed in rat, dog, pig, and monkey, demonstrating properties consistent with progression to human studies. [3]

MCC7840 exhibited lower human ether-à-go-go-related gene (hERG) ion channel inhibition compared to MCC950, suggesting a reduced risk of cardiotoxicity. [3]
In vitro metabolism and toxicology studies revealed similar profiles for MCC7840 and MCC950, with the notable exception of improved cardiac safety for MCC7840. [3]
In the MWS mouse model, MCC7840 was well tolerated at all doses tested (up to 30 mg/kg every other day), with no overt signs of toxicity. [3]
In the 6-OHDA and PFF-Syn mouse models, chronic oral administration of MCC7840 (via gavage or drinking water for up to 12 months) was well tolerated, with no treatment-related adverse effects reported. [3]
Off-target safety screening confirmed that MCC7840 was devoid of activity in a broad panel of binding, enzyme, kinase, and cell-based assays, indicating high selectivity. [3]

[1]. Inhibiting the NLRP3 Inflammasome. Molecules. 2020 Nov 25;25(23):5533.

[2]. Sulfonylureas and related compounds and use of same. WO2016131098A1.

[3]. PET-MRI biomarkers reveal efficacy of a novel NLRP3 inhibitor in Parkinson's disease models. Brain. 2025 Oct 16:awaf372.

Background: MCC7840 (also known as Inzomelid or Emlenoflast) is a novel, potent, and selective NLRP3 inflammasome inhibitor developed to overcome the limitations of MCC950, which had suboptimal pharmacokinetics and safety concerns. It was selected as a lead candidate based on its superior pharmacokinetics, target engagement, and preclinical safety properties. [3]
Mechanism of action: MCC7840 directly binds to the NACHT domain of NLRP3, blocking ATP hydrolysis and preventing inflammasome assembly. This inhibits caspase-1 activation, thereby blocking the maturation and release of IL-1β and IL-18, and preventing pyroptotic cell death. [3]
Clinical development: MCC7840 has completed Phase I randomized, double-blinded, placebo-controlled, single and multiple ascending dose clinical trials in healthy subjects (NCT04015076), demonstrating excellent safety, tolerability, and pharmacokinetic profile. Related analogues have also shown safety in humans (NCT04086602). [3]
Therapeutic potential: This study demonstrates that MCC7840 is efficacious in preclinical models of Parkinson's disease, even when administered therapeutically after symptom onset, and reduces neuroinflammation as measured by PET/MRI biomarkers. These findings support its potential as a disease-modifying therapy for Parkinson's disease and possibly other NLRP3-driven neurodegenerative disorders. [3]
PET/MRI biomarkers: The study utilized a multi-tracer PET/MRI approach in the same animal to assess neuroinflammation (¹⁸F-DPA-714), dopamine transporter availability (¹⁸F-FBCTT), dopamine synthesis (¹⁸F-FDOPA), and blood-brain barrier integrity (gadolinium MRI), providing a non-invasive toolkit to monitor drug efficacy and target engagement in living subjects. [3]

C19H23N4NAO3S

410.4657

410.138

2380032-29-9

Emlenoflast;1995067-59-8

155971211

White to off-white solid powder

1

5

4

28

649

0

S(C1C([H])=C([H])N(C([H])(C([H])([H])[H])C([H])([H])[H])N=1)([N-]C(N([H])C1=C2C([H])([H])C([H])([H])C([H])([H])C2=C([H])C2C([H])([H])C([H])([H])C([H])([H])C=21)=O)(=O)=O.[Na+]

RKEFKQUKINZXDR-UHFFFAOYSA-M

InChI=1S/C19H24N4O3S.Na/c1-12(2)23-10-9-17(21-23)27(25,26)22-19(24)20-18-15-7-3-5-13(15)11-14-6-4-8-16(14)18;/h9-12H,3-8H2,1-2H3,(H2,20,22,24);/q;+1/p-1

sodium;1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl-(1-propan-2-ylpyrazol-3-yl)sulfonylazanide

MCC7840 sodium; Emlenoflast sodium; 2380032-29-9; Emlenoflast (sodium); sodium;1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl-(1-propan-2-ylpyrazol-3-yl)sulfonylazanide;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product is not stable in solution, please use freshly prepared working solution for optimal results.  (2). Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~240 mg/mL (~584.70 mM)

Solubility in Formulation 1: ≥ 6 mg/mL (14.62 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 60.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 6 mg/mL (14.62 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 60.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 6 mg/mL (14.62 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 60.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)