cariporide (Hoe-642) / Sanofi - LARVOL DELTA

Sodium glucose co-transporter 2 inhibitor empagliflozin prevents endothelial dysfunction induced by oscillatory shear stress. (PubMed, Biomed Pharmacother) - "EMPA prevents OSS induced ROS generation by the inhibition of the NHE1/NCX/Ca2+ axis. The suppression of OSS-induced ROS generation by EMPA contributes to improved endothelial barrier function of endothelial cells but has limited effect on the inflammatory response in HCAECs subjected to OSS."

Journal • Inflammation • CDH5 • ICAM1

Catecholamines induce endothelial dysfunction to promote pro-inflammatory and pro-thrombotic responses: role of the NADPH oxidases/SGLT2 pro-oxidant pathway (HEART FAILURE 2025) - " Human microvascular endothelial cells (HMEC-1) were exposed to either epinephrine (Epi), isoproterenol, dobutamine or norepinephrine...No such effects were observed with Na+/H+ exchanger inhibitor cariporide. This study reveals that catecholamines adversely affect endothelial function via NADPH oxidases/SGLT2, resulting in eNOS-NO/ROS imbalance, increased glucose uptake, procoagulant activity and inflammation. Targeting the NADPH oxidases/SGLT2 pathway may provide new therapeutic strategies to enhance endothelial function and cardiovascular outcomes in patients with elevated catecholamines."

Cardiovascular • Congestive Heart Failure • Heart Failure • CDKN1A • ICAM1 • IL18 • IL1B • IL6 • NOS3 • NOX4 • TNFA • VCAM1

Novel sodium-hydrogen exchanger 1 inhibitors with diphenyl ketone scaffold: Design, Synthesis, mechanism and evaluation in mice model of heart failure. (PubMed, Eur J Med Chem) - "Cell viability assay and pH recovery experiment based on H9c2 cells were conducted and compound 7g was found to have equal NHE1 inhibitory activity to cariporide (0.64 μM) with the IC50 values of 0.78 μM. In vivo, compared with the clinically approved drug empagliflozin (30 mg/kg), 7g alleviated left ventricular systolic dysfunction in a heart failure model induced by isoproterenol (ISO) at lower concentration (10 mg/kg). In summary, this study supplies a promising lead compound with novel scaffold for NHE1 inhibitor and also provide a feasible strategy for HF drug discovery."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Metabolic Disorders

PHARMACOLOGICAL INHIBITION OF NA/H EXCHANGER ISOFORM 1 ATTENUATES ALZHEIMER'S DISEASE PATHOGENESIS IN APP/PS1 MICE (ADPD 2025) - "We then tested the effic acy of pharmacological inhibition of NHE1 with its inhibitor HOE642 in attenuating AD pathology in APP mice... In summary, we detected NHE1 protein upregulation in reactive astrocytes in AD brains. Pharmacological inhibition of NHE1 protein attenuated pathological A β fibril oligomer density and hyperactive locomotor behaviors in APP mice, emerging as a potential ea rly therapeutic target for AD."

Preclinical • Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Inflammation • Ischemic stroke • Mood Disorders • Psychiatry • FAP • GFAP

Sodium-glucose co-transporters (SGLT2) inhibitors prevent lipid droplets formation in vascular inflammation or lipid overload by SGLT2-independent mechanism. (PubMed, Biomed Pharmacother) - "This is the first report demonstrating that SGLT2-I prevent the formation of LDs in the vasculature. Empagliflozin downregulates LDs formation in vascular inflammation or lipid overload via an SGLT2-independent mechanism. Empagliflozin's protective effects involve the NHE1/PKC/NOX pathway in the TNF response but not in the OA response."

Journal • Diabetes • Inflammation • Metabolic Disorders • Oncology • ICAM1

Empagliflozin Mitigates High Glucose-Disrupted Mitochondrial Respiratory Function in H9c2 Cardiomyoblasts: A Comparative Study with NHE-1 and ROCK Inhibition. (PubMed, Curr Mol Pharmacol) - "In comparison, Rho/ROCK and NHE-1 inhibitions effectively prevent ROS overproduction, while SGLT2 inhibition rescues the deteriorated mitochondrial respiratory function under diabetogenic conditions. Blockade of SGLT2, NHE-1, or Rho/ROCK activity is useful for the prevention of diabetic cardiomyopathy."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Diabetes • Heart Failure • Metabolic Disorders • RHOA

Upregulation of Na/H Exchanger in Astrogliosis and Early Alzheimer's Disease Pathogenesis. (PubMed, Aging Dis) - "We then tested the efficacy of pharmacological NHE1 inhibition using its inhibitor, HOE642, in attenuating pathogenesis in APP mice...In summary, we detected NHE1 protein upregulation in reactive astrocytes in both AD human and APP brains. Pharmacological inhibition of NHE1 protein attenuated pathological Aβ plaque density, and hyperactive locomotor behaviors in APP mice, highlighting NHE1 as a possible therapeutic target for AD."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Inflammation • Ischemic stroke • FAP • GFAP

Sodium-Glucose Cotransporter 2 inhibitor Empagliflozin Enhances Autophagy and Reverses Remodeling in Hearts with Large, Old Myocardial Infarctions. (PubMed, Eur J Pharmacol) - "These effects were similar to those of the NHE-1 inhibitor cariporide, suggesting a possibility that they both act on the same pathway. Empagliflozin is a beneficial pharmacological tool that enhances autophagy to reverse remodeling in the postinfarction heart."

Journal • Cardiovascular • Congestive Heart Failure • Diabetes • Fibrosis • Heart Failure • Immunology • Metabolic Disorders • Myocardial Infarction • CTSD • mTOR

Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents. (PubMed, Nat Prod Bioprospect) - "Among all target compounds at 1 μM, compounds 9d, 9f, 9k, 9m, and 9n, with a protection ratio exceeding 30%, exerted stronger protective effects on H9c2 cardiomyocyte than positive control dexrazoxane and buthutin A. Meanwhile, compounds 9k, 9m, and 9o showed the significant NHE-1 inhibitory activities on H9c2 cardiomyocyte, all with a dpHi/min value less than 0.23. Molecular modelling studies suggested the ability of compounds 9m and 9o to establish interactions with three hydrogen bonds to Asp267 and Glu346 of NHE-1, but also the ability with much lower CDOCKER energies than positive control cariporide and buthutin A. The structure-activity relationship (SAR) studies suggested that the presences of amide group, four-carbon linker, and para hydroxyl benzene ring were advantageous pharmacophores for above two pharmacological actions. This research would open new avenues for developing amide-guanidine-based cardioprotective agents."

Journal • Cardiovascular

Empagliflozin treatment rescues abnormally reduced Na+ currents in ventricular cardiomyocytes from dystrophin-deficient mdx mice (ESC 2024) - "In a second experimental approach, peak INa was compared after a 24 hour exposure of isolated mdx ventricular cardiomyocytes with 1 µM EMPA, 10 µM of the Na+-H+ exchanger 1 inhibitor cariporide, or 10 µM cariporide in combination with 1 µM EMPA. Our findings indicate that EMPA treatment can correct abnormally reduced peak INa of dystrophin-deficient ventricular cardiomyocytes. Long-term EMPA administration may diminish arrhythmia vulnerability in DMD patients."

Preclinical • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure

Crucial role for sensory nerves and Na/H exchanger inhibition in dapagliflozin and empagliflozin-induced arterial relaxation. (PubMed, Cardiovasc Res) - "SGLT2 inhibitors relax mesenteric arteries by promoting the release of CGRP from sensory nerves in a NHE1-dependent manner."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

Na+/H+-exchange inhibition by cariporide is compensated via Na+,HCO3--cotransport and has no net growth consequences for ErbB2-driven breast carcinomas. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "In conclusion, acute administration of cariporide ex vivo powerfully inhibits net acid extrusion from breast cancer tissue but lowers steady-state pHi minimally. Prolonged cariporide administration in vivo is compensated via NBCn1 and we observe no discernible effect on growth of ErbB2-driven breast carcinomas."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • SLC4A7

Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2. (PubMed, Basic Res Cardiol) - "In vivo treatment with the specific NHE1-inhibitor Cariporide mimicked the protection by EMPA, without additional protection by EMPA. On the other hand, in vivo inhibition of NOS with L-NAME deteriorated HF and prevented protection by EMPA. In conclusion, the data support that the beneficial effects of EMPA are mediated through the NHE1-NO pathway in TAC/DOCA-induced heart failure and not through SGLT2 inhibition."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology

NHE1 Protein in Repetitive Mild TBI-Mediated Neuroinflammation and Neurological Function Impairment. (PubMed, Antioxidants (Basel)) - "However, post-r-mTBI administration of a potent NHE1 inhibitor, HOE642, attenuated locomotor and cognitive functional deficits as well as pathological signatures of gliosis, oxidative stress, axonal damage, and white matter damage. These findings indicate NHE1 upregulation plays a role in r-mTBI-induced oxidative stress, axonal damage, and gliosis, suggesting NHE1 may be a promising therapeutic target to alleviate mTBI-induced injuries and restore neurological function."

Journal • CNS Disorders • Cognitive Disorders • Inflammation • Solid Tumor • Vascular Neurology • APP • FAP • GFAP • OLIG2

Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF. (PubMed, Cardiovasc Res) - "We show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late INa and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late INa, which could contribute to antiarrhythmic effects in patients with HFpEF."

Journal • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure • HDAC4 • NAV1

Blocking H+ Extrusion Protein Reduces Gliosis and Functional Impairment in Experimental Concussion Model (AAN 2024) - "These findings imply that concussion-mediated NHE1 protein increase may play a role in the development of axonal damage, neuroinflammation, and neuronal function impairments. Pharmacological inhibition of NHE1 shows protective effects."

CNS Disorders • Inflammation • Vascular Neurology • APP • GFAP

Empagliflozin mitigates cardiac hypertrophy through cardiac RSK/NHE-1 inhibition. (PubMed, Biomed Pharmacother) - "RSK inhibition by EMPA appears as a novel direct cardiac target of SGLT2i. Direct cardiac effects of EMPA exert their anti-hypertrophic effect through NHE-inhibition and subsequent RSK pathway inhibition."

Journal

Myometrium infection decreases TREK1 through NHE1 and increases contraction in pregnant mice. (PubMed, Am J Physiol Cell Physiol) - "The NHE1 inhibitor cariporide was used to explore to the effect of NHE1 on TREK1...Furthermore, suppression of NHE1 with siRNA transfection inhibited the contractility of uterine smooth muscle cells, and activate the TREK1. Altogether, our findings indicate that infection increases the uterine contraction by down-regulating myometrium TREK1 in mice, and the inhibition of TREK1 is attributed to the activation of NHE1."

Journal • Preclinical • Infectious Disease

Acidosis defense mechanisms in the preimplantation stages of embryos in BALB/c strain mice. (PubMed, Theriogenology) - "Specific inhibitors such as cariporide (1 μM), S3226 (1 and 10 μM), EIPA (1, 5, and 25 μM), and amiloride (1 mM) were used to functionally identify NHE isoforms, and the nonspecific inhibitor 4,4'-diisocyanatostilbene-2,2' disulphonic acid, disodium salt (DIDS) was used to confirm NDBCE activity. NDBCE has a supportive function in all embryonic stages, especially in the PN zygote and the 2-c embryo. Preimplantation stage embryos have effective mechanisms to defend against acidosis in response to their metabolic end products (increased acid load) and the acidic environment in utero."

Journal • Preclinical • Metabolic Disorders

Ion Transport and Inhibitor Binding by Human NHE1: Insights from Molecular Dynamics Simulations and Free Energy Calculations. (PubMed, J Phys Chem B) - "Our MD simulations involving NHE1 inhibitors (cariporide and amiloride analogues) maintained stable interactions with Asp267 and Glu346. Our study highlights the importance of the salt bridge between the positively charged acylguanidine moiety and Asp267, which appears to play a role in the competitive inhibitory mechanism for this class of inhibitors. Our computational study provides a detailed mechanistic interpretation of experimental data and serves the basis of future structure-based inhibitor design."

Journal • Oncology

Empagliflozin prevents oxidative stress in human coronary artery endothelial cells via the NHE/PKC/NOX axis. (PubMed, Redox Biol) - "EMPA reduced NOX activity via attenuation of the NHE/Na/NCX/Ca/PKC axis, leading to less ROS generation in HCAECs exposed to 10 % stretch."

Journal • PRKCB

Assessing the Therapeutic Efficacy of Proton Transport Inhibitors in a Triple-Negative Breast Cancer Murine Model with Magnetic Resonance Imaging-Chemical Exchange Saturation Transfer Tumor pH Imaging. (PubMed, Metabolites) - "Cell viability and extracellular pH assays were carried out in breast cancer cells cultured at physiological pH (7.4) or acid-adapted (pH of 6.5 and 6.8) following the exposure to inhibitors of V-ATPase (Lansoprazole, Esomeprazole) or NHE1 (Amiloride, Cariporide) at several concentrations. A significant reduction in tumor volume, prolonged survival, and increase in extracellular tumor pH after 1 and 2 weeks were observed after Lansoprazole treatment, whereas no significant changes were detected upon Amiloride treatment. Our results suggested that MRI-CEST tumor pH imaging can monitor the therapeutic efficacy of PPIs in breast cancer murine models."

Journal • MRI • Preclinical • Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • Triple Negative Breast Cancer

Acid-base homeostasis orchestrated by NHE1 defines pancreatic stellate cell phenotype in pancreatic cancer. (PubMed, JCI Insight) - "Indeed, tumor fibrosis decreased when mice received the NHE1-inhibitor cariporide in addition to gemcitabine treatment. Moreover, the tumor immune infiltrate shifts from granulocyte-rich to more lymphocytic. Taken together, our study provides mechanistic evidence on how the pancreatic pH landscape shapes pancreatic cancer through tuning PSC differentiation."

Journal • Fibrosis • Gastrointestinal Cancer • Hepatology • Immunology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CAFs

Pharmacological Inhibition of NHE1 Protein Increases White Matter Resilience and Neurofunctional Recovery after Ischemic Stroke. (PubMed, Int J Mol Sci) - "In this study, we tested the efficacy of two potent NHE1 inhibitors, HOE642 and Rimeporide, with a delayed administration regimen starting at 24 h post-stroke in adult C57BL/6J mice. The pharmacological blockade of NHE1 protein activity reduced microglia inflammatory responses and enhanced oligodendrogenesis and white matter repair, leading to motor and cognitive function recovery after stroke. Our study reveals the potential of targeting NHE1 protein as a therapeutic strategy for ischemic stroke therapy."

Journal • Cardiovascular • Inflammation • Ischemic stroke • Solid Tumor

Cariporide, a Selective Na+-H+ Exchange Inhibitor, Enhances Cardiac Positive Inotropic and Lusitropic Responses to Dobutamine in Heart Failure: Assessment by Pressure-Volume Analysis (AHA 2022) - "In pacing-induced HF, Na+-H+ exchange inhibition by cariporide enhances LV positive inotropic and lusitropic responses to DOB. This suggests that combination therapy with intravenous cariporide and DOB may be appropriate in HF, thus providing a potential method of enhancing β-adrenergic responsiveness of the failing myocardium."

Cardiovascular • Congestive Heart Failure • Heart Failure • Metabolic Disorders • EDN1