Delving into the Latest Updates on Cariporide mesilate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Cariporide, HOE 604, HOE 642

+ [2]

Target

NHE1

Mechanism

NHE1 inhibitors(Sodium/hydrogen exchanger 1 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System Disorders

Active Indication

Colorectal Cancer

Inactive Indication

Angina, UnstableArrhythmias, CardiacMyocardial Infarction

Originator Organization

Sanofi

Active Organization

Brown University

Inactive Organization

SanofiAventis SA

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure

Molecular FormulaC13H21N3O6S2

InChIKeyFNDLQABGYJQJPH-UHFFFAOYSA-N

CAS Registry159138-81-5

Sodium/glucose transporter 2 (SGLT2 or SLC5A2) inhibitors lower blood glucose and are also approved treatments for heart failure independent of raised glucose. Various studies have showed that SGLT2 inhibitors relax arteries, but the underlying mechanisms are poorly understood and responses variable across arterial beds. We speculated that SGLT2 inhibitor-mediated arterial relaxation is dependent upon calcitonin gene-related peptide (CGRP) released from sensory nerves independent of glucose transport.

Methods and results:

The functional effects of SGLT1 and 2 inhibitors (mizagliflozin, dapagliflozin, and empagliflozin) and the sodium/hydrogen exchanger 1 (NHE1) blocker cariporide were determined on pre-contracted resistance arteries (mesenteric and cardiac septal arteries) as well as main renal conduit arteries from male Wistar rats using wire myography. SGLT2, CGRP, TRPV1, and NHE1 expression was determined by western blot and immunohistochemistry. Kv7.4/5/KCNE4 and TRPV1 currents were measured in the presence and absence of dapagliflozin and empagliflozin. All SGLT inhibitors (1–100 µM) and cariporide (30 µM) relaxed mesenteric arteries but had negligible effect on renal or septal arteries. Immunohistochemistry with TRPV1 and CGRP antibodies revealed a dense innervation of sensory nerves in mesenteric arteries that were absent in renal and septal arteries. Consistent with a greater sensory nerve component, the TRPV1 agonist capsaicin relaxed mesenteric arteries more effectively than renal or septal arteries. In mesenteric arteries, relaxations to dapagliflozin, empagliflozin, and cariporide were attenuated by the CGRP receptor antagonist BIBN-4096, depletion of sensory nerves with capsaicin, and blockade of TRPV1 or Kv7 channels. Neither dapagliflozin nor empagliflozin activated heterologously expressed TRPV1 channels or Kv7 channels directly. Sensory nerves also expressed NHE1 but not SGLT2 and cariporide pre-application as well as knockdown of NHE1 by translation stop morpholinos prevented the relaxant response to SGLT2 inhibitors.

Conclusion:

SGLT2 inhibitors relax mesenteric arteries by promoting the release of CGRP from sensory nerves in a NHE1-dependent manner.

31 Jul 2024·CARDIOVASCULAR RESEARCH

Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF

Article

Author: Heers, Silvia ; Schmid, Christof ; Reuthner, Kathrin ; Arzt, Michael ; Wagner, Stefan ; Lebek, Simon ; Schollmeier, Elisa ; Hamdani, Nazha ; Provaznik, Zdenek ; Keller, Karoline ; Riechel, Johannes ; Trum, Maximilian ; Wester, Michael ; Hegner, Philipp ; Klatt, Susanne ; Maier, Lars

Abstract:

Aims:

Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodelling and atrial fibrillation are frequently observed in HFpEF. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have recently been shown to improve clinical outcomes in HFpEF, and post-hoc analyses suggest atrial anti-arrhythmic effects. We tested if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx, which is known to cause atrial arrhythmias, and if that is responsive to treatment with the SGTL2i empagliflozin.

Methods and results:

Cardiomyocytes were isolated from atrial biopsies of 124 patients (82 with HFpEF) undergoing elective cardiac surgery. Na influx was measured with the Na-dye Asante Natrium Green–2 AM (ANG-2). Compared to patients without heart failure (NF), Na influx was doubled in HFpEF patients (NF vs. HFpEF: 0.21 ± 0.02 vs. 0.38 ± 0.04 mmol/L/min (N = 7 vs. 18); P = 0.0078). Moreover, late INa (measured via whole-cell patch clamp) was significantly increased in HFpEF compared to NF. Western blot and HDAC4 pulldown assay indicated a significant increase in CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation in HFpEF compared to NF, whereas NaV1.5 protein and mRNA abundance remained unchanged. Consistently, increased Na influx was significantly reduced by treatment not only with the CaMKII inhibitor autocamtide-2-related inhibitory peptide (AIP), late INa inhibitor tetrodotoxin (TTX) but also with sodium/hydrogen exchanger 1 (NHE1) inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late INa in HFpEF. Multivariate linear regression analysis, adjusting for important clinical confounders, revealed HFpEF to be an independent predictor for changes in Na handling in atrial cardiomyocytes.

Conclusion:

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 anti-arrhythmic effects in patients with HFpEF.

01 May 2024·Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

Empagliflozin mitigates cardiac hypertrophy through cardiac RSK/NHE-1 inhibition

Article

Author: Zuurbier, Coert J ; Coronel, Ruben ; Ghouse, Zakiya ; Weber, Nina C ; Overberg, Kenneth ; Hollmann, Markus W ; Chen, Sha

BACKGROUND:

SGLT2i reduce cardiac hypertrophy, but underlying mechanisms remain unknown. Here we explore a role for serine/threonine kinases (STK) and sodium hydrogen exchanger 1(NHE1) activities in SGLT2i effects on cardiac hypertrophy.

METHODS:

Isolated hearts from db/db mice were perfused with 1 µM EMPA, and STK phosphorylation sites were examined using unbiased multiplex analysis to detect the most affected STKs by EMPA. Subsequently, hypertrophy was induced in H9c2 cells with 50 µM phenylephrine (PE), and the role of the most affected STK (p90 ribosomal S6 kinase (RSK)) and NHE1 activity in hypertrophy and the protection by EMPA was evaluated.

RESULTS:

In db/db mice hearts, EMPA most markedly reduced STK phosphorylation sites regulated by RSKL1, a member of the RSK family, and by Aurora A and B kinases. GO and KEGG analysis suggested that EMPA inhibits hypertrophy, cell cycle, cell senescence and FOXO pathways, illustrating inhibition of growth pathways. EMPA prevented PE-induced hypertrophy as evaluated by BNP and cell surface area in H9c2 cells. EMPA blocked PE-induced activation of NHE1. The specific NHE1 inhibitor Cariporide also prevented PE-induced hypertrophy without added effect of EMPA. EMPA blocked PE-induced RSK phosphorylation. The RSK inhibitor BIX02565 also suppressed PE-induced hypertrophy without added effect of EMPA. Cariporide mimicked EMPA's effects on PE-treated RSK phosphorylation. BIX02565 decreased PE-induced NHE1 activity, with no further decrease by EMPA.

CONCLUSIONS:

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.

100 Deals associated with Cariporide mesilate

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB06468

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Angina, Unstable	Phase 3	DE	Aventis SA	-
Angina, Unstable	Phase 3	-	-	-
Angina, Unstable	Phase 3	-	Sanofi	-
Myocardial Infarction	Phase 3	DE	Aventis SA	-
Myocardial Infarction	Phase 3	-	-	-
Myocardial Infarction	Phase 3	-	Sanofi	-
Arrhythmias, Cardiac	Phase 2	DE	Aventis SA	-
Colorectal Cancer	Preclinical	US	Brown University	01 Jul 2021