A label‐free impedance assay in endothelial cells differentiates the activation and desensitization properties of clinical S1P<sub>1</sub> agonists

Grailhe, P.; Boutarfa-Madec, Asma; Beauverger, Philippe; Janiak, Philip; Parkar, Ashfaq A

doi:10.1002/2211-5463.12951

Cited by 10 publications

(12 citation statements)

References 34 publications

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“…SAR247799 is a G-protein-biased S1P 1 agonist (inhibiting adenylate cyclase preferentially over activation of β-arrestin and internalization pathways) with endothelial-protective properties in rats and pigs at doses that do not desensitize S1P 1, namely non-lymphocyte-reducing doses. 50,51 In healthy subjects, SAR247799 has an attractive safety, tolerability and pharmacokinetics (PK) profile and the dose-response relationship for lymphocyte pharmacodynamics (PD) has been characterized. 52 Although preclinical studies with SAR247799 showed protective effects in the renal and coronary vasculature in a preventative setting using single doses administered prior to an insult of ischaemia/reperfusion-induced endothelial injury, the effect of chronic administration of SAR247799 on the endothelium is currently unknown.…”

Section: What This Study Addsmentioning

confidence: 99%

“…In preclinical models, SAR247799 is a biphasic molecule that can activate S1P 1 with endothelial-protective properties at low doses, while causing lymphocyte reduction, like other S1P 1 -desensitizing molecules, at higher doses. 50,51 Biological activities often follow the 4-parameter logistic model in which E max is related to dose (i.e. the bigger the dose, the larger the effect), 53 and with this assumption, many proof-of-concept trials test a single dose, at-or-close-to the maximum tolerated dose.…”

Section: What This Study Addsmentioning

confidence: 99%

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Endothelial‐protective effects of a G‐protein‐biased sphingosine‐1 phosphate receptor‐1 agonist, SAR247799, in type‐2 diabetes rats and a randomized placebo‐controlled patient trial

Bergougnan

Andersen

Plum‐Mörschel

et al. 2020

Brit J Clinical Pharma

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agonist designed to activate endothelial S1P 1 and provide endothelial-protective properties, while limiting S1P 1 desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P 1 activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation. Methods: Type-2 diabetes patients, enriched for endothelial dysfunction (flowmediated dilation, FMD <7%; n = 54), were randomized, in 2 sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. Endothelial function was assessed by brachial artery FMD. Renal function, biomarkers and lymphocytes were measured following 5-week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing. Results: The maximum FMD change from baseline vs placebo for all treatments was reached on day 35; mean differences vs placebo were 0.60% (95% confidence interval [CI] −0.34 to 1.53%; P = .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%; P = .026) for 5 mg SAR247799 and 0.88% (95% CI −0.15 to 1.91%; P = .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal-to-no lymphocyte reduction and small-to-moderate heart rate decrease. The authors confirm that the Principal Investigators for the clinical study were Grit Anderson and Leona Plum-Mörschel and that they had direct clinical responsibility for patients at the Neuss and Mainz sites, respectively. In addition, Grit Andersen was coordinating principal investigator.

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Section: What This Study Addsmentioning

confidence: 99%

Section: What This Study Addsmentioning

confidence: 99%

Endothelial‐protective effects of a G‐protein‐biased sphingosine‐1 phosphate receptor‐1 agonist, SAR247799, in type‐2 diabetes rats and a randomized placebo‐controlled patient trial

Bergougnan

Andersen

Plum‐Mörschel

et al. 2020

Brit J Clinical Pharma

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“…fingolimod, siponimod and ozanimod) or are in clinical development for immuno-inflammatory disorders, they were all developed as S1P 1 functional antagonists that cause peripheral blood lymphopenia through S1P 1 desensitization. In contrast, SAR247799 is a G-protein-biased S1P 1 agonist, preferentially activating G-protein over β-arrestin and internalization signaling pathways and activates S1P 1 without causing desensitization [15]. SAR247799 thus exhibits endothelial-protective properties without reducing lymphocytes [16].…”

Section: Introductionmentioning

confidence: 98%

A G-protein-biased S1P1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

Evaristi¹,

Poirier²,

Chénedé³

et al. 2022

PLoS ONE

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Aim Heart failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with no approved treatment. Left ventricular hypertrophy (LVH) and diastolic dysfunction represent the structural and functional components of HFpEF, respectively. Endothelial dysfunction is prevalent in HFpEF and predicts cardiovascular events. We investigated if SAR247799, a G-protein-biased sphingosine-1-phosphate receptor 1 (S1P1) agonist with endothelial-protective properties, could improve cardiac and renal functions in a rat model of metabolic syndrome LVH and diastolic function. Methods 31- and 65-week-old obese ZSF1 (Ob-ZSF1) rats, representing adult and aged animals with LVH and diastolic dysfunction, were randomized to a chow diet containing 0.025% (w/w) of SAR247799, or control (CTRL) chow for 4 weeks. Age-matched lean ZSF1 (Le-ZSF1) rats were fed control chow. Echocardiography, telemetry, biochemical and histological analysis were performed to evaluate the effect of SAR247799. Results Echocardiography revealed that Ob-ZSF1 rats, in contrast to Le-ZSF1 rats, developed progressive diastolic dysfunction and cardiac hypertrophy with age. SAR247799 blunted the progression of diastolic dysfunction in adult and aged animals: in adult animals E/e’ was evaluated at 21.8 ± 1.4 for Ob-ZSF1-CTRL, 19.5 ± 1.2 for Ob-ZSF1-SAR247799 p<0.01, and 19.5 ± 2.3 for Le-ZSF1-CTRL (median ± IQR). In aged animals E/e’ was evaluated at 23.15 ± 4.45 for Ob-ZSF1-CTRL, 19.5 ± 5 for Ob-ZSF1-SAR247799 p<0.01, and 16.69 ± 1.7 for Le-ZSF1-CTRL, p<0.01 (median ± IQR). In aged animals, SAR247799 reduced cardiac hypertrophy (g/mm mean ± SEM of heart weight/tibia length 0.053 ± 0.001 for Ob-ZSF1-CTRL vs 0.046 ± 0.002 for Ob-ZSF1-SAR247799 p<0.01, Le-ZSF1-CTRL 0.035 ± 0.001) and myocardial perivascular collagen content (p<0.001), independently of any changes in microvascular density. In adult animals, SAR247799 improved endothelial function as assessed by the very low frequency bands of systolic blood pressure variability (mean ± SEM 67.8 ± 3.41 for Ob-ZSF1-CTRL 55.8 ± 4.27 or Ob-ZSF1-SAR247799, p<0.05 and 57.3 ± 1.82 Le-ZSF1-CTRL), independently of any modification of arterial blood pressure. In aged animals, SAR247799 reduced urinary protein/creatinine ratio, an index of glomerular injury, (10.3 ± 0.621 vs 8.17 ± 0.231 for Ob-ZSF1-CTRL vs Ob-ZSF1-SAR247799, respectively, p<0.05 and 0.294 ± 0.029 for Le-ZSF1-CTRL, mean ± SEM) and the fractional excretion of electrolytes. Circulating lymphocytes were not decreased by SAR247799, confirming lack of S1P1 desensitization. Conclusions These experimental findings suggest that S1P1 activation with SAR247799 may be considered as a new therapeutic approach for LVH and diastolic dysfunction, major components of HFpEF.

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“…fingolimod, siponimod and ozanimod) or are in clinical development for immuno-inflammatory disorders, they were all developed as S1P 1 functional antagonists that cause peripheral blood lymphopenia through S1P 1 desensitization. In contrast, SAR247799 is a G-protein-biased S1P 1 agonist, preferentially activating G-protein over βarrestin and internalization signaling pathways and activates S1P 1 without causing desensitization (14). SAR247799 thus exhibits endothelial-protective properties without reducing lymphocytes (15).…”

Section: Introductionmentioning

confidence: 98%

“…Despite efforts to explore the effects of some endothelial-based therapies in the components of HFpEF, there is no confirmation at present that restoring endothelial function would provide clinical improvements in the progression of the components of HFpEF. We therefore set out to test whether 4-week oral treatment with the S1P 1 agonist, SAR247799, a molecule that we have previously shown has endothelial protective effects in animals and humans (14)(15)(16)(17) improves cardiac structural and functional parameters in a rat model of LVH and diastolic function. We used the diabetic Zucker fatty spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat, carrying two separate leptin receptor mutations (fa and facp), which has been described as a genetically-hypertensive, obese and diabetic model of HFpEF (18,19).…”

Section: Introductionmentioning

confidence: 99%

A G-protein-biased S1P₁ agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

Evaristi

Poirier

Chénedé

et al. 2021

Preprint

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Aim: Heart failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with no approved treatment. Left ventricular hypertrophy (LVH) and diastolic dysfunction represent the structural and functional components of HFpEF, respectively . Endothelial dysfunction is prevalent in HFpEF and predicts cardiovascular events. We investigated if SAR247799, a G-protein-biased sphingosine-1-phosphate receptor 1 (S1P 1 ) agonist with endothelial-protective properties, could improve cardiac and renal functions in a rat model of metabolic syndrome LVH and diastolic function. Methods: 31- and 65-week-old obese ZSF1 (Ob-ZSF1) rats, representing young and old animals with LVH and diastolic dysfunction, were randomized to a chow diet containing 0.025% (w/w) of SAR247799, or control (CTRL) chow for 4 weeks. Age-matched lean ZSF1 (Le-ZSF1) rats were fed control chow. Echocardiography, telemetry, biochemical and histological analysis were performed to evaluate the effect of SAR247799. Results: Echocardiography revealed that Ob-ZSF1 rats, in contrast to Le-ZSF1 rats, developed progressive diastolic dysfunction and cardiac hypertrophy with age. SAR247799 blunted the progression of diastolic dysfunction in young and old animals: in young animals E/e’ was evaluated at 21.8 ± 1.4 for Ob-ZSF1-CTRL, 19.5 ± 1.2 for Ob-ZSF1-SAR247799 p<0.01, and 19.5 ± 2.3 for Le-ZSF1-CTRL (median ± IQR). In old animals E/e’ was evaluated at 23.15 ± 4.45 for Ob-ZSF1-CTRL, 19.5 ± 5 for Ob-ZSF1-SAR247799 p<0.01, and 16.69 ± 1.7 for Le-ZSF1-CTRL, p<0.01 (median ± IQR). In old animals, SAR247799 reduced cardiac hypertrophy (mean ± SEM of heart weight/tibia length 0.053 ± 0.001 for Ob-ZSF1-CTRL vs 0.046 ± 0.002 for Ob-ZSF1-SAR247799 p<0.01, Le-ZSF1-CTRL 0.035 ± 0.001) and myocardial perivascular collagen content (p<0.001), independently of any changes in microvascular density. In young animals, SAR247799 improved endothelial function as assessed by the very low frequency bands of systolic blood pressure variability (mean ± SEM 67.8 ± 3.41 for Ob-ZSF1-CTRL 55.8 ± 4.27 or Ob-ZSF1-SAR247799, p<0.05 and 57.3 ± 1.82 Le-ZSF1-CTRL), independently of any modification of arterial blood pressure. In old animals, SAR247799 reduced urinary protein/creatinine ratio, an index of glomerular injury, (10.3 ± 0.621 vs 8.17 ± 0.231 for Ob-ZSF1-CTRL vs Ob-ZSF1-SAR247799, respectively, p<0.05 and 0.294 ± 0.029 for Le-ZSF1-CTRL, mean ± SEM) and the fractional excretion of electrolytes. Circulating lymphocytes were not decreased by SAR247799, confirming lack of S1P 1 desensitization. Conclusions: These experimental findings suggest that S1P 1 activation with SAR247799 could improve LVH, cardiac diastolic and renal function in HFpEF patients .

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A label‐free impedance assay in endothelial cells differentiates the activation and desensitization properties of clinical S1P₁ agonists

Cited by 10 publications

References 34 publications

Endothelial‐protective effects of a G‐protein‐biased sphingosine‐1 phosphate receptor‐1 agonist, SAR247799, in type‐2 diabetes rats and a randomized placebo‐controlled patient trial

Endothelial‐protective effects of a G‐protein‐biased sphingosine‐1 phosphate receptor‐1 agonist, SAR247799, in type‐2 diabetes rats and a randomized placebo‐controlled patient trial

A G-protein-biased S1P1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

A G-protein-biased S1P₁ agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

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A label‐free impedance assay in endothelial cells differentiates the activation and desensitization properties of clinical S1P1 agonists

Cited by 10 publications

References 34 publications

Endothelial‐protective effects of a G‐protein‐biased sphingosine‐1 phosphate receptor‐1 agonist, SAR247799, in type‐2 diabetes rats and a randomized placebo‐controlled patient trial

Endothelial‐protective effects of a G‐protein‐biased sphingosine‐1 phosphate receptor‐1 agonist, SAR247799, in type‐2 diabetes rats and a randomized placebo‐controlled patient trial

A G-protein-biased S1P1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

A G-protein-biased S1P1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

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A label‐free impedance assay in endothelial cells differentiates the activation and desensitization properties of clinical S1P₁ agonists

A G-protein-biased S1P₁ agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome