WO2025002914A1 - Antagonistes du récepteur 1 de l'imidazoline destinés à être utilisés dans la prévention et/ou le traitement d'une maladie auto-inflammatoire ou auto-immune - Google Patents

Antagonistes du récepteur 1 de l'imidazoline destinés à être utilisés dans la prévention et/ou le traitement d'une maladie auto-inflammatoire ou auto-immune Download PDF

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WO2025002914A1
WO2025002914A1 PCT/EP2024/066950 EP2024066950W WO2025002914A1 WO 2025002914 A1 WO2025002914 A1 WO 2025002914A1 EP 2024066950 W EP2024066950 W EP 2024066950W WO 2025002914 A1 WO2025002914 A1 WO 2025002914A1
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imp
atherosclerosis
antagonist
autoinflammatory
autoimmune disease
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Annalaura MASTRANGELO
Iñaki ROBLES VERA
David Sancho Madrid
Borja IBAÑEZ CABEZA
Valentín FUSTER CARULLA
Diego MAÑANES
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Centro Nacional De Investigaciones Cardiovasculares Carlos Iii (fsp)
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Centro Nacional De Investigaciones Cardiovasculares Carlos Iii (fsp)
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention is of application in the medical science, in particular in the diagnosis and treatment of autoinflammatory and autoimmune diseases, preferably atherosclerosis.
  • CVDs cardiovascular diseases
  • AT atherosclerosis
  • the identification and diagnosis of AT is mainly based on imaging examinations, being arteriography the gold standard for its diagnosis.
  • advances in medical imaging techniques have improved the detection of AT
  • the high cost and the challenges in large-scale screening has highlighted the need for cost- effective clinical markers to be used, optionally combined with other known AT risk factors.
  • Atherosclerosis is a chronic disease in which lipids build up in arteries causing local inflammation and the development of atheroma plaques. These plaques, which are infiltrated by immune cells, can impede blood flow and eventually cause blood clots due to their rupture leading to coronary artery disease or ischemic cerebrovascular disease.
  • LDL low-density lipoprotein
  • macrophages can also show a proinflammatory phenotype that promotes the secretion of cytokines and chemokines and amplifies the immune response by recruiting monocytes, T cells and neutrophils.
  • Imidazole propionate is a downstream metabolite of histidine generated by the gut microbiota and associated with insulin resistance.
  • T2D type-2 diabetes
  • T2D type-2 diabetes
  • Molinaro has disclosed ImP associated with heart failure and mortality (Molinaro A. et al. Microbially Produced Imidazole Propionate is Associated with Heart Failure and Mortality, JACC Heart Failure, 2023, Article in press). The document is focused on prognosis and heart function. Heart failure is a clinical condition completely different from atherosclerosis; Diagnosis, prognosis, treatment, and causes of death are completely different between heart failure and atherosclerosis. There are very well-established biomarkers for heart failure (e.g. BNP) with no role at all in atherosclerosis, neither in subclinical stages nor in transition to acute coronary syndromes.
  • BNP biomarkers for heart failure
  • Atherosclerosis e.g., LDL cholesterol
  • transition of atherosclerosis to acute coronary syndromes e.g., CK MB
  • Both conditions refer to the cardiovascular field but the fact that the metabolite is found in late stages of a disease does not imply that ImP can be a priori associated with early stages that may or not result on such a disease (in this case, atherosclerosis and heart failure). Therefore, the document does not teach or suggest the use of ImP as a biomarker for subclinical atherosclerosis.
  • ImP is rather listed as a metabolite significantly different between all Coronary Artery Disease (CAD) cases vs controls (Table 6, underlying statistic is a non-parametric test) and naive CAD and controls (Table 10, underlying statistic is a non-parametric test) but, for instance, was not included in the Figures of metabolomics variables that are predictive for probability of CAD (Tables 11 , 12, 15, 16, 20 & 21 , underlying statistic is ROC curve analysis).
  • Authors state that only the metabolomic variables predictive for probability of CAD should be included in the Figure of potential biomarkers of the disease, thereby teaching away from the use of ImP as biomarker for AT.
  • Lipid-lowering therapy has been used for decades in AT, with statins being the therapy of choice both in primary and secondary prevention for cardiovascular diseases.
  • statins being the therapy of choice both in primary and secondary prevention for cardiovascular diseases.
  • some subjects still have cardiovascular disease risk following statin therapy, despite achieving LDL-cholesterol targets.
  • Alternative pharmacological agents have been proposed over the years to address this limitation, the majority of them targeting lipid metabolism and also anti-inflammatory drugs.
  • the number of adverse effects, the cost and the need of parenteral administration have limited their use to specific cases and generally in combination with statins.
  • WO 2005/039639 A2 describe pharmaceutical compositions comprising selective imidazole receptor agonists combined with angiotensin II receptor blockers for the treatment of hypertension, especially in hypertensive patients already suffering from type II diabetes.
  • a positive agonistic action on medullary I1 R alone is sufficient to reduce blood pressure.
  • I1 R agonists are involved in the inhibition of the sympathetic nervous system to inhibit vasomotor tone and thereby lowering the blood pressure.
  • l1 R-antagonist agents like AGN 192403 provoke the opposite effect; although AGN 192403 in particular is wrongly mentioned as an “agonist” in many references when in fact it is acting as “antagonist” (Head, G. A. & Mayorov, D. N.
  • Imidazoline receptors novel agents and therapeutic potential
  • Cardiovasc. Hematol. Agents Med Chem. 4, 17- 32, 2006 AGN 192403 acting as ligand of I1 R has no effect on blood pressure, let alone that a drug targeting hypertension should not be a priori related to atherosclerosis.
  • Atherosclerosis cannot be confused with other cardiovascular pathologies that may be treated with anti-hypertensive agents; in fact, lipid-lowering therapies typically used for atherosclerosis would not have any effect on hypertension.
  • Rll 2734281 C1 describes a composition for treating arterial hypertension and associated cardiovascular pathologies comprising a 11-imidazoline receptor agonist selected from moxonidine and rilmenidine, providing synergy with an p-adrenoreceptor blocking agent.
  • the authors reported a more effective control of myocardial contractility and reduction of the risk of calcium overload of working cardiomyocytes, preventing the development of pathophysiological events in the heart.
  • Moxonidine and rilmenidine are not selective for I1 R, though, since they act through the a2-adrenergic receptor in the proposed mechanism. In any case and as stated above, the reported effect is achieved with a positive agonist effect on the receptor, whereas the document is silent about an eventual antagonist effect of a selective ligand to 11 R.
  • the problem of the art can be formulated as providing a molecular way of treating autoimmune and autoinflammatory diseases, including atherosclerosis.
  • the solution proposed by the present invention is the use of antagonists of the lmidazoline-1 receptor (I1 R).
  • the present invention refers to an antagonist of imidazoline-1 receptor (I1 R), or a pharmaceutically acceptable salt, tautomer, solvate, diastereomer, enantiomer, or prodrug thereof, wherein as valence and stability permit, for use in the prevention and/or treatment of an autoinflammatory or autoimmune disease in a human subject, in which said antagonist is ( ⁇ )-2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane (synonym: AGN 192403), N-benzylguanidine, 2-(2-Fluoro-5-methylphenyl)-4,5-dihydro-1 H- imidazole (synonym: S23757), 2-(2-chloro-4-iodo-phenylamino)-5-methyl-pyrroline (synonym: LNP911), 1-(4, 5-dihydro-1 H-imidazol-2-yl)isoquinoline (synonym:
  • a preferred aspect of the invention is that said autoinflammatory or autoimmune disease is atherosclerosis.
  • said human patient has a level of ImP in blood of at least 41 nM, preferably between 41 nM and 266 nM.
  • Another aspect of the invention is a method of treatment of an autoinflammatory or autoimmune disease comprising administering an antagonist of the I1 R in a patient in need thereof, preferably one of the antagonist compounds mentioned above.
  • Another preferred aspect is a pharmaceutical composition
  • a pharmaceutical composition comprising an antagonist of I1 R, in combination of at least one pharmaceutically suitable excipient.
  • Still a further aspect of the invention is a method for screening and/or producing therapeutic candidates for the prevention and/or treatment of an autoinflammatory or autoimmune disease, comprising in-vitro assessing whether a therapeutic candidate is able to inhibit the binding of ImP to I1 R, wherein a positive result indicates that the therapeutic candidate is useful for the treatment of said autoinflammatory or autoimmune disease.
  • the present application confirms the microbial origin of ImP while revealing a direct correlation with increased atherosclerosis (Fig.1). This direct correlation of higher ImP metabolite in plasma with increased active subclinical atherosclerosis in healthy volunteers is also found in a human cohort (Fig. 2). In addition, the inventors have discovered that ImP is not only associated with atherosclerosis (AT) but is also causal for the progression of the disease (Fig 3).
  • the inventors have observed that ImP-induced atherosclerosis is associated systemically with increased inflammation and locally with an activation of fibroblasts, macrophages and endothelial cells in aorta (Fig 4).
  • the mechanism of action of ImP further implicates a role in other autoimmune diseases by showing a remarkable enrichment of T cells and B cells in the aorta upon treatment with ImP (Fig 4).
  • the data provided in the present application establish a clear link between ImP-induced AT and the induction of innate and adaptive immune responses, strongly indicating a potential causal role for ImP in additional autoinflammatory and autoimmune diseases not limited to atherosclerosis.
  • the present invention demonstrates that ImP treatment triggered TNFa production and mTOR pathway activation in mouse aortic endothelial cells ECs (MAECs), bone marrow derived macrophages (BMDM) and in murine-embryonary fibroblasts (MEFs) (Fig.5).
  • MAECs mouse aortic endothelial cells ECs
  • BMDM bone marrow derived macrophages
  • MEFs murine-embryonary fibroblasts
  • Stimulation of MAECs, BMDMs and MEFs with ImP in the presence of imidazoline receptor (IR) ligands showed that only AGN 192403 (I1 R antagonist) blocked the effect mediated by ImP (Fig.6).
  • the present invention describes a novel therapy based on the blockage of this axis that is able to prevent atherosclerosis and, more remarkably, to treat it independently of the metabolism of lipids, the established risk factor for atherosclerosis (Fig.7 and 8).
  • the present invention refers to compounds as selective ligands for 11 R that therefore do not or only scarcely interact with a2-adrenoreceptor and I2R for the treatment of atherosclerosis and other autoimmune and autoinflammatory diseases.
  • the compounds have to be antagonists of I1 R.
  • a “ligand of the receptor” is understood to be an inorganic or organic molecule capable of interacting and of antagonist effect on the activation of the receptor, or any other agent capable of negatively impacting the biological function of the receptor.
  • a “selective ligand” is understood to be a ligand acting directly in the receptor while maintaining selectivity over potential off-targets.
  • Another aspect of the invention proposes a personalized therapy based on the identification of individuals with high levels of ImP in the blood that are more likely to benefit from the inhibition of this specific axis. Indeed, it has been observed that ImP levels are significantly increased in subjects with subclinical AT when compared to controls. Moreover, higher levels of ImP in the bloodstream were also associated with increased risk of having AT, which held true after adjusting for traditional risk factors, including total cholesterol, hypertension, current smoking, among others (Fig. 2). This additionally indicates that the ImP level in bloodstream can serve as a biomarker of subclinical AT.
  • the inventors further describe the discriminative performance of ImP to detect early AT when the ImP is considered alone or combined with features associated with AT (i.e. , familial hypercholesterolemia, familiar history of cardiovascular disease, active smoking, hypertension, hemoglobin and creatinine in blood) (Fig. 2).
  • ImP performed better in discriminating subjects with early AT when compared to markers and scores routinely used in the clinics (e.g., LDL-cholesterol in blood and others) (Fig. 2), even in terms of sensitivity and specificity when the clinically recommended cut-off is used.
  • Another aspect of the invention is the use of ImP in the diagnosis of an autoinflammatory or autoimmune disease in a biological sample obtained from a subject, preferably AT.
  • said biological sample is a is a blood sample or a plasma sample.
  • Another preferred aspect of the present invention is a method of diagnosis of AT, comprising assessing the level of ImP in a blood or plasma sample obtained from a human subject, and determining whether said level is above or below a value of 41 nM, wherein a value above 41 nM is indicative of likelihood of having early AT.
  • said level of ImP is between 41 and 266 nM.
  • Still another aspect of the invention is a method of detecting ImP in a blood or plasma sample obtained from a subject having or at risk of an autoinflammatory or autoimmune disease, preferably AT, the method comprising detecting a level of ImP in a blood or plasma sample collected from the subject and determining whether the level of ImP is above or below a value of 41 nM.
  • said method is liquid chromatography coupled with mass spectrometry (LCMS).
  • LCMS mass spectrometry
  • diagnosis is understood as the prediction of atherosclerosis when no symptoms are yet detectable in a healthy subject.
  • the invention includes a method of diagnosing the subject as being more likely to have AT by assessing the level of ImP in a blood sample of said subject, and determining whether said level in the bloodstream is above or below a value of 41 nM, wherein a value above 41 nM is indicative of the subject more likely having early AT.
  • ImP is associated with and can be complementary to features of early atherosclerosis.
  • another preferred aspect of the invention is the use of ImP in combination with other risk factors to diagnose atherosclerosis at a subclinical stage where the confounding effects of other comorbidities are limited.
  • other biological variables to count on are familiar history of CVDs, hypertension, current smoking, hemoglobin, creatinine and familial hypercholesterolemia.
  • Figure 1 shows how ImP is associated with atherosclerosis in ApoEKO mice.
  • ApoEKO male (8 weeks old) mice were fed different diets (chow, high cholesterol (HC), and HC & high choline (HC/HC) for 8 weeks.
  • HC/HC high cholesterol
  • a cocktail of antibiotics including ampicillin (1 mg/ml), neomycin (1 mg/ml), metronidazole (1mg/ml) and vancomycin (0.5mg/ml) was added (or not) in the drinking water to deplete microbiota.
  • FIG. 2 shows how ImP is increased in subjects with subclinical atherosclerosis.
  • Arithmetic mean ⁇ SEM of each group is shown. **p ⁇ 0.005, vs. healthy subjects by Mann-Whitney II test.
  • Model 1 OR was adjusted for age, sex and active smoking.
  • Model 2 was adjusted for Model 1 plus glucose (fasting), high-sensitivity C-reactive protein and hemoglobin levels. Squares represent OR and the upper and lower whisker the 95 % confidence intervals (Cl), *p ⁇ 0.05, **p ⁇ 0.01 , ***p ⁇ 0.001. I— Unadjusted, ⁇ Model 1 , ⁇ Model 2.
  • Variables in the Figure are ImP, FHCVD, HTN, current smoking, hemoglobin, creatinine and familial hypercholesterolemia.
  • Figure 3 shows how ImP is able to induce atherosclerosis.
  • Figure 3a - ImP supplementation to the drinking water induces AT in ApoE' /_ male mice that were fed chow diet for 8 weeks (+/- ImP) after weaning
  • Figure 4 shows how ImP induces innate and adaptive responses that promote inflammation and immunity.
  • Figure 4c LIMAP embedding of whole aorta-derived cells based on transcriptomic profiles after 8 weeks under chow diet (control) or chow diet + ImP (ImP) colored by cell type.
  • Figure 4d Cell proportions obtained from scRNA-seg data comparing control vs ImP conditions.
  • FIG. 4f Heat map of Gene set enrichment analysis (GSEA) for Macrophages (MFs), Fibroblasts (FBs) and endothelial cells (ECs). Kolmogorov Smirnov test was performed. Unpaired Student's t test between Ctrol and ImP; *p ⁇ 0.05; **p ⁇ 0.01 , unless otherwise stated.
  • GSEA Gene set enrichment analysis
  • Figure 5 shows how mTOR activation in immune cells contributes to ImP-induced inflammatory response and atherosclerosis.
  • FIGs 5a, 5b - Mouse aortic ECs (MAECs), murine-embryonary fibroblasts (MEFs) and bone marrow derived MFs (BMDM) were treated 24h in vitro with ImP (ImP, 10 pg/mL) or not (Ctrol) co-incubated with Rapamycin (10nM).
  • ImP ImP
  • MEFs murine-embryonary fibroblasts
  • BMDM bone marrow derived MFs
  • Figure 6 shows how Imidazoline 1 receptor activation mediated the proinflammatory profile generate by ImP on several cell types.
  • Figures a, b provide graphs showing the key role of mTOR activation and Imidazoline 1 receptor as clue in the in vitro induction of proinflammatory cytokines and mTOR activation induce by ImP in several cell types.
  • FIGs 6a, 6b - Mouse aortic ECs (MAECs), bone marrow derived MFs (BMDM) and in murine-embryonary fibroblasts (MEFs) were treated in vitro with ImP (ImP, 10 pg/mL) or not (Ctrol) co-incubated with Rapamycin (10nM, mTOR1 antagonist) AGN192403 (10 pg/mL, I1 R antagonist), Idazoxan (0.06 pg/mL, IR and a2 antagonist) or Yohimbine (1 pg/mL, a2 antagonist).
  • Rapamycin and AGN192403 co-incubations were able to block the induction of TNFa production and Phospho-S6 activation induce by ImP.
  • Figure 7 shows how ImP mediates its effect on atherosclerosis through the imidazoline receptor 1.
  • Figures a, b provide evidence showing the key role of Imidazoline 1 receptor in vivo as mediator of atherogenic plaque induced by ImP, and the independency of changes in total cholesterol and Ldl cholesterols in this effect.
  • Figures c-e show the clue role of Imidazoline 1 receptor in the systemic inflammation induce by ImP, determinate by the reduction of proinflammatory cells population, Figure a, the blocking of increase of proinflammatory cytokines, Figure d, and the prevention of mTOR pathway activation in macrophages, Figure e.
  • Figures f, g show the capacity of Imidazoline 1 receptor to mediate the aorta inflammation induce by ImP,
  • Figure 7c - Ly6C high monocytes, and Th1 cell on blood, from ApoE -/- mice treated 8 weeks with ImP +- AGN192403 on the drinking water. Data are pooled from three independent experiments, n 15.
  • Figure 7f, 7g - Th1/Treg ratio and b) changes in Th1 and Treg population infiltrated in aorta in ApoE -/- mice treated with ImP +- AGN 192403 fed with chow diet for 8 weeks. n 7-9. Individual data and mean ⁇ SEM from indicated independent experiments is shown unless otherwise stated. One-way ANOVA was performed (Tukey correction). * p ⁇ 0.05; ** p ⁇ 0.01 ; *** p ⁇ 0.005.
  • Figure 8. shows how the inhibition of the l1 R/lmP pathway prevents atherosclerosis progression.
  • Figures a, b provide evidence showing Imidazoline 1 receptor blocking in vivo as target receptor to atherogenic plague induce by High Cholesterol diet, and the independency of changes in total cholesterol and Ldl cholesterols in this effect.
  • Figures c-f show Imidazoline 1 receptor as a target to reduce the systemic inflammation in AT: Figures c-d, determined by the reduction of proinfl am matory cells population; Figure e, the reduction of proinflammatory cytokines; and Figure f, the reduction of mTOR pathway activation in macrophages.
  • mice were fed different diets (chow, high cholesterol) for 8 weeks.
  • One-way ANOVA was performed (Tukey correction). * p ⁇ 0.05; ** p ⁇ 0.01 ; *** p ⁇ 0.005; **** p ⁇ 0.001.
  • Atherosclerosis we fed ApoE-KO mice (8 weeks old) different diets: chow, high cholesterol (H, 10% fat, 0.75% chol) and HC-high choline (HC/HC, HC+ 1% choline) for 8 weeks.
  • Plasma samples were collected at different times after overnight fasting, and the heart and aorta at sacrifice as indicated (Fig.1 . Figure a).
  • mice were perfused with 10 ml of Phosphate Buffered Saline (PBS) via cardiac puncture to remove blood contamination from vascular tissue.
  • PBS Phosphate Buffered Saline
  • the aortas were dissected and fixed in formaldehyde 4% w/w (PanReac, AppliChem) overnight. Then, the exposed aortas were stained for lipid depositions with Oil Red O (Sigma-Aldrich), and an end face assay was performed. Images were taken with a Leica Nikon camera magnifier and an atherosclerotic lesion in the aorta was measured using Imaged software.
  • HC diets (HCDs) induced atherosclerosis, which in the HC/HC group was significantly reduced in the presence of abx (Fig.1. Figure b), suggesting that AT progression in this model depends on microbiota.
  • the host plasma metabolome was analyzed by untargeted metabolomics to identify novel metabolites associated with AT and/or microbiota. Specifically, proteins were removed from plasma samples, which were collected at culling, by adding a cold (-20°C) mixture of Methanol: Ethanol (1 :1 , v/v) in a ratio 5:1 (solventsample) and by storing the samples on ice for 20 minutes. Blank sample was prepared following the same extraction procedure, adding only the solvents to a 1.5 mL Eppendorf tube. Samples and blank were centrifuged at 16400 g for 20 minutes 4°C and the supernatant was transferred in a 1.5 mL Eppendorf tube.
  • Metabolomics untargeted analysis was performed using a Ultimate 3000 HPLC system consisting of a degasser, two binary pumps, and thermostatic autosampler, maintained at 8°C (ThermoFisher Scientific) coupled to a LTQ Orbitrap XLTM Hybrid Ion Trap- Orbitrap Mass Spectrometer (ThermoFisher Scientific).
  • MS/MS spectra were collected in data-dependent mode via higher-energy C-trap dissociation (HCD) in the orbitrap. Samples were analyzed in a randomized order. Generated data was firstly aligned using Compound Discoverer (ThermoFisher Scientific); signals were extracted and grouped into features (isotopic traces from a single analyte at a particular charge state) using the Metaboprofiler node in Compound discoverer (the open-source plug-in freely available from OpenMS (Rost HL, et al. OpenMS: a flexible open-source software platform for mass spectrometry data analysis. Nat Methods. 30;13(9):741-8, 2016).
  • Compound Discoverer ThermoFisher Scientific
  • Signals were extracted and grouped into features (isotopic traces from a single analyte at a particular charge state) using the Metaboprofiler node in Compound discoverer (the open-source plug-in freely available from OpenMS (Rost HL, et al
  • Imidazole propionate was revealed as a microbiota-dependent - metabolite (Fig.1. Figure g) that positively correlated with atherosclerosis (Fig.1. Figure h).
  • the annotation of ImP was confirmed by MS/MS spectra comparison between the experimental feature corresponding to ImP and its standard both acquired in a subsequent LC/MS/MS analysis that was carried out using the same chromatographic conditions outlined previously (Fig.1. Figure i).
  • 18 F-FDG Fluorodeoxyglucose
  • LC-MS-based targeted metabolomics was used to quantify ImP and its related metabolites (i.e., histidine and urocanic acid) in plasma samples. Specifically, proteins were precipitated by adding a cold (-20°C) mixture of Methanol: Ethanol (1 :1 , v/v) in a ratio 2:1 (solventsample) and by storing the samples on ice for 20 minutes. Samples were centrifuged at 16400 g for 20 minutes 4°C and the supernatant was transferred in in the insert of the LC-MS vial.
  • reaction monitoring transitions were as follows: 141 >123 (10) and 141 >81 (26) for ImP; 139>121 (10) and 139> 93 (26) for urocanic acid; 142>124 (10) and 142> 41 (26) for labeled urocanic acid; 156>110 (10) and 156 > 83 (30), for histidine; and, 159>113 (10) and 159 > 86 (30) for labeled histidine.
  • Quantification of ImP concentration was performed by generating a standard curve with known concentrations of this metabolite. Histidine and urocanic acid were instead quantified by using internal standards added to the plasma samples as stated above. Metabolite standards were analyzed alongside the plasma samples using the LC-MS/MS method. The dilution of the plasma during the sample preparation was also considered for the quantification.
  • ImP levels were significantly increased in subjects with subclinical atherosclerosis when compared to controls, but not histidine or urocanic acid levels (Fig. 2a-c). Moreover, a higher concentration of ImP was associated with increased risk of having AT calculated using multinomial logistic regression. Odds ratio and confidence (Cl) interval were provided showing that increased ImP levels were significantly associated (P ⁇ 0.05) with higher risk of AT also after adjusting for AT traditional risk factors (Fig. 2c). Remarkably, in our cohort, ImP levels were more strongly associated with active rather than inactive AT, with AT_BM and AT_SYS being the groups with the strongest association between ImP and increased risk of AT (Fig. 2b-c).
  • ROC curve analysis was used to assess the discriminative performance of ImP to diagnose a subject more likely to have subclinical AT.
  • ImP showed an ALIROC equal to 0.58 (95% confidence interval (Cl): 0.52-0.64, P ⁇ 0.01) (Fig. 2d) that increased up to 0.75 (95% Cl: 0.70-0.80, P ⁇ 0.0001) when ImP is combined with features selected according to the LASSO method (i.e., familial hypercholesterolemia, familiar history of cardiovascular disease, active smoking, hypertension, hemoglobin and creatinine in blood) (Fig. 2e).
  • ImP 400ug/mL was supplied in the drinking water of chow-fed ApoE ⁇ mice for 8 weeks. After treatment, blood was collected, and mice were perfused with 10 ml of Phosphate Buffered Saline (PBS) via cardiac puncture to remove blood contamination from vascular tissue. The aortas were dissected and fixed in formaldehyde 4% w/w (PanReac, AppliChem) overnight.
  • PBS Phosphate Buffered Saline
  • Example 4 ImP induces innate and adaptive responses that promote inflammation and immunity.
  • ImP The effect of ImP on the immune cells were analyze by flow cytometry (FACS). Single cells blood suspension was stained for 30 min at 4°C with LIVE/DEAD Fixable Aqua Dead Cell Stain Kit (Life Technologies). After washing with PBS, cells were stained in FACS buffer containing anti-CD16/32 (BioXcell), 3% FBS and 0.05% EDTA with the corresponding antibody cocktail for 30 min on ice. ImP induced an expansion of pro- inflammatory Ly6C hi monocytes (CD45+Ly6C+), T-helper 17 (Th17)
  • RNA sequencing (scRNA-seq) analysis of the whole aorta was performed from chow-fed ApoE ⁇ mice administered ImP for 4 or 8 weeks.
  • the aortas were collected and kept in cold Dulbecco's Modified Eagle Medium (DMEM) to be digested.
  • DMEM Dulbecco's Modified Eagle Medium
  • Perivascular fat was removed and the thoracic aortic with arch was open longitudinally and chopped.
  • the chopped aorta was incubated for 30 min at 37°C in water bath in digestion buffer (Collagenase A (25 mg/ml), (Roche/Sigma #10103586001).
  • Dispase II 25 mg/ml
  • DNase I 250 pg/ml
  • elastase 25ul/ml
  • Liberase TL 0.2 Wunsch units/mL
  • Each sample was labeled with a cell multiplexing oligo (CMO) using a CMO labeling for Single Cell RNA Sequencing Protocol from 10x Genomics.
  • CMO cell multiplexing oligo
  • Cells labeled with CMOs were washed, labelled with SytoxGreen and Hoescht to ensure cell viability and live cells sorted with a FACs Aria cell sorter.
  • Samples were pooled and single-cell RNA-seq was performed following the Chromiun Next GEM Single Cell 3’ v3.1 with feature barcode technology for cell multiplexing protocol (10x Genomics). Briefly, cells were first counted and checked their viability using Countess 3 cell counter (Thermofisher).
  • cells were first counted and checked their viability using Countess 3 cell counter (Thermofisher). Next, cells were loaded onto a 10x Genomics chip of the Chromium Controller (10x Genomics). After cDNA amplification, gene expression and CMO libraries were generated and sequenced using an Illumina NextSeq 2000 sequencer.
  • Raw sequencing data processing was performed from FASTQ file from each port using Cell Ranger (v6.1.2) with default parameters and the mm10 (GRCm38.p6) mouse genome reference provided by 10x Genomics. Obtained raw unique molecular identifier (UMI) count matrices of valid barcoded cells for each port were loaded into R (v4.1.2) for further analyses using Bioconductor packages (Amezquita RA, et al. Orchestrating single-cell analysis with Bioconductor. Nat Methods. 2020 Feb; 17(2): 137-145. doi: 10.1038/s41592-019-0654-x) and Seurat (v4.0.6) (Hao Y, et al. Integrated analysis of multimodal single-cell data. Cell.
  • UMI raw unique molecular identifier
  • Elbow plot method was used to determine the number of PCs for downstream analyses (25 PCs). Then, cells were clustered using the Louvain algorithm for modularity optimization using KNN graph as input and visualized using the Uniform Manifold Approximation and Projection for Dimension Reduction (UMAP) algorithm with the first 25 principal components as input. Main clusters were identified by using known markers and calculating differentially expressed genes with Wilcoxon-rank sum test using presto R package (v1.0.0); Extended Data Fig.4). Cell proportions were calculated for each condition and time point in every cell population, and a two-proportions Z-test using the prop. test R function was chosen to determine significance.
  • UMAP Uniform Manifold Approximation and Projection for Dimension Reduction
  • Fig. 4c Based on unsupervised graph-based clustering algorithm and manual annotation by classical markers seven clusters were defined according to their gene expression profiles (Fig 4c), highlighting a significant decrease in the proportions of vascular smooth cells 1 and a significant increase in fibroblasts (FBs), endothelial cells (ECs) and immune cells populations, particularly after 8 weeks of ImP supplementation (Fig. 4d). Moreover, focusing on the immune cell compartment, at 8 weeks, a remarkable enrichment of T cells (logFC: +3.12, C vs ImP, P ⁇ 0.00001) and B cells (logFC: +4.61 , C vs ImP, P ⁇ 0.00001) in the aorta of ApoE ⁇ fed chow diet when treated with ImP, which was also confirmed by FACS (Fig.
  • a gene set enrichment analysis for each cluster was performed by comparing cells from mice treated or not with ImP, pointing out an increased expression of genes related to inflammation, in particular to the TNFa signaling via the NFKB pathway, being associated with ImP treatment in all cell types (Fig. 4f).
  • Example 5 mTOR activation in immune cells contributes to ImP-induced inflammatory response and atherosclerosis.
  • Mouse embryonic fibroblast (MEF) cell lines were isolated from 13.5 dpc from embryos using standard protocol. Each embryo was dissected into 10ml of sterile PBS, voided of its internal organs, head, and legs. After 30 min incubation with gentle shaking at 37°C with 5ml 0,1% trypsin, cells were plated in two 100 mm dishes and incubated for 24-48h.
  • Mouse aortic endothelial cells MAECs were isolated from mouse thoracic aortas as described previously (REF).
  • the cells were cultured (Medium 199 (Gibco, Invitrogen Life Technologies) + 20% fetal bovine serum + Penicillin/Streptomycin 2 mM + Glutamine 2 mM + HEPES 10 mM + endothelial cell growth supplement 30 Ig/mL + Heparin 100 mg/mL, all from Sigma-Aldrich, under 5% CO2 at 370.
  • Murine BMDMs were generated as previously described 13 with some modifications.
  • BM cells from WT C57BL/6J mice were cultured in RPMI 1640 supplemented with 30% M-CSF obtained from L929 cell line and 10% FBS, 100 pg ml -1 penicillin, 100 pg ml -1 streptomycin, 10 mM HEPES, 1 nM sodium pyruvate (all from Gibco) during 5 days in sterile, but not tissue-culture treated, 10-cm Petri dishes. Cultured MEF, MAECs and BMDM were plated in equal number (1x10 5 cells per well) in 96-well plates (200-pl final volume, Corning) and rested overnight.
  • BMDM and MEF were stimulated with ImP in the presence of AGN192403 (10 pg/mL, I1 R ligand with antagonist functions), idazoxan (0.06 pg/mL, IR antagonist with high affinity for I2R), or yohimbine (1 pg/mL, a potent a2-adrenoceptor antagonist with low affinity for IRs).
  • AGN192403 10 pg/mL, I1 R ligand with antagonist functions
  • idazoxan (0.06 pg/mL, IR antagonist with high affinity for I2R
  • yohimbine (1 pg/mL, a potent a2-adrenoceptor antagonist with low affinity for IRs.
  • the AGN 192403 treatment dampened the systemic inflammation and the adaptive response induced by ImP, specifically by reducing the expansion of Ly6C hi monocytes and Th1 cells.
  • the concentration of pro-inflammatory cytokines, INFy and TN Fa was measure in the serum according manufactures protocol using Mouse IFN- gamma DuoSet ELISA (DY485), respectably and Mouse TNF-alpha DuoSet ELISA (DY410). INFy and TNFa were found normalized by AGN192403.
  • AGN 192403 treatment inhibited the activation of the mTOR pathway in peritoneal macrophages (Fig. 7e).
  • Fig. 7f Th1/Treg polarization
  • the disease was induced by feeding ApoE ⁇ mice with HC diet for 8 weeks, thereby increasing the ImP production (Fig. 1g).
  • Mice were supplemented with AGN 192403 during the last 4 weeks on diet. It resulted in a reduction in the atheroma plaque in the treated mice (Fig. 8a) without effect on total cholesterol or LDL-C (Fig. 8b) alongside a systemic reduction in Ly6C hi monocytes (Fig. 8c) as well as a normalization of Th1 cells numbers in blood (Fig. 8d) and pro-inflammatory cytokine concentration IFNy measured (Fig. 8e) Moreover, the treatment reduced the activation of mTOR in peritoneal macrophages (Fig. 8f). Notably, this protective effect occurred despite the increased cholesterol levels in the bloodstream of HC-fed mice.

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Abstract

La présente invention concerne un antagoniste du récepteur 1 de l'imidazoline (I1R) destiné à être utilisé dans la prévention et/ou le traitement d'une maladie auto-inflammatoire ou auto-immune chez un sujet humain, choisi dans le groupe consistant en (±)-2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane (synonyme : AGN192403), N-benzylguanidine, 2-(2-fluoro-5-méthylphényl)-4,5-dihydro-1H-imidazole (synonyme : S23757), 2-(2-chloro-4-iodo-phénylamino)-5-méthyl-pyrroline (synonyme : LNP911), 1-(4, 5-dihydro-1H-imidazol-2-yl) isoquinoline (synonyme : BU98008), 5-[2-bromophénoxy)méthyl]-4,5-dihydro-1,3-oxazol-2-amine (synonyme : S23515), 6-méthylamino-2méthylheptène (synonyme : isométheptène), et acide 4-chloro-2,3-dihydro-2-oxo-1,3-benzothiazol-3-ylacétique (synonyme : bénazoline). L'invention concerne également l'utilisation du propionate d'imidazole dans le diagnostic d'une maladie auto-inflammatoire ou auto-immune chez un sujet, ainsi qu'une méthode de diagnostic de l'athérosclérose comprenant l'évaluation du taux d'ImP dans un échantillon de sang et la détermination visant à savoir si ledit taux est supérieur ou inférieur à une valeur de 41 nM.
PCT/EP2024/066950 2023-06-26 2024-06-18 Antagonistes du récepteur 1 de l'imidazoline destinés à être utilisés dans la prévention et/ou le traitement d'une maladie auto-inflammatoire ou auto-immune Ceased WO2025002914A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN120899684A (zh) * 2025-10-11 2025-11-07 中国人民解放军军事科学院军事医学研究院 Brd4780作为抗志贺毒素保护剂的用途及其相关产品
CN120899684B (zh) * 2025-10-11 2025-12-16 中国人民解放军军事科学院军事医学研究院 Brd4780作为抗志贺毒素保护剂的用途及其相关产品

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