Publications by authors named "Ashfaq A Parkar"

5 Publications

  • Page 1 of 1

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

PLoS One 2022 14;17(1):e0257929. Epub 2022 Jan 14.

Diabetes and Cardiovascular Research, Sanofi US Services, Bridgewater, NJ, United States of America.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257929PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759645PMC
January 2022

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.

Br J Clin Pharmacol 2021 05 26;87(5):2303-2320. Epub 2020 Nov 26.

Sanofi US Services, Bridgewater, NJ, USA.

Aims: SAR247799 is a G-protein-biased sphingosine-1 phosphate receptor-1 (S1P ) agonist designed to activate endothelial S1P and provide endothelial-protective properties, while limiting S1P desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P 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 (flow-mediated 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.

Conclusion: These data provide the first human evidence suggesting endothelial-protective properties of S1P activation, with SAR247799 being as effective as the clinical benchmark, sildenafil. Further clinical testing of SAR247799, at sub-lymphocyte-reducing doses (≤5 mg), is warranted in vascular diseases associated with endothelial dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.14632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247405PMC
May 2021

A label-free impedance assay in endothelial cells differentiates the activation and desensitization properties of clinical S1P agonists.

FEBS Open Bio 2020 10 4;10(10):2010-2020. Epub 2020 Sep 4.

Diabetes and Cardiovascular Research, Sanofi US Services, Bridgewater, NJ, USA.

Sphingosine-1 phosphate receptor-1 (S1P ) activation maintains endothelial barrier integrity, whereas S1P desensitization induces peripheral blood lymphopenia. The latter is exploited in the approval and/or late-stage development of receptor-desensitizing agents targeting the S1P receptor in multiple sclerosis, such as siponimod, ozanimod, and ponesimod. SAR247799 is a recently described G protein-biased S1P agonist that activates S1P without desensitization and thus has endothelial-protective properties in patients without reducing lymphocytes. As SAR247799 demonstrated endothelial-protective effects at sub-lymphocyte-reducing doses, the possibility exists that other S1P modulators could also exhibit endothelial-protective properties at lower doses. To explore this possibility, we sought to quantitatively compare the biased properties of SAR247799 with the most advanced clinical molecules targeting S1P . In this study, we define the β-arrestin pathway component of the impedance profile following S1P activation in a human umbilical vein endothelial cell line (HUVEC) and report quantitative indices of the S1P activation-to-desensitization ratio of various clinical molecules. In a label-free impedance assay assessing endothelial barrier integrity and disruption, the mean estimates (95% confidence interval) of the activation-to-desensitization ratios of SAR247799, ponesimod, ozanimod, and siponimod were 114 (91.1-143), 7.66 (3.41-17.2), 6.35 (3.21-12.5), and 0.170 (0.0523-0.555), respectively. Thus, we show that SAR247799 is the most G protein-biased S1P agonist currently characterized. This rank order of bias among the most clinically advanced S1P modulators provides a new perspective on the relative potential of these clinical molecules for improving endothelial function in patients in relation to their lymphocyte-reducing (desensitization) properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/2211-5463.12951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530392PMC
October 2020

First-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of SAR247799, a selective G-protein-biased sphingosine-1 phosphate receptor-1 agonist for endothelial protection.

Br J Clin Pharmacol 2021 02 8;87(2):598-611. Epub 2020 Jul 8.

Sanofi US Services, Bridgewater, NJ, USA.

Aims: SAR247799 is a selective G-protein-biased sphingosine-1 phosphate receptor-1 (S1P ) agonist with potential to restore endothelial function in vascular pathologies. SAR247799, a first-in-class molecule differentiated from previous S1P -desensitizing molecules developed for multiple sclerosis, can activate S1P without desensitization and consequent lymphopenia. The aim was to characterize SAR247799 for its safety, tolerability, pharmacokinetics and pharmacodynamics (activation and desensitization).

Methods: SAR247799 was administered orally to healthy subjects in a double-blind, randomized, placebo-controlled study with single (2.5-37.5 mg) or 2-week once-daily (0.5-15 mg) doses. An open-label single dose pilot food-interaction arm with 10 mg SAR247799 in cross-over design was also performed.

Results: SAR247799 was well tolerated and, at the higher end of the dose ranges, caused the expected dose-dependent pharmacodynamics associated with S1P activation (heart rate reduction) and S1P desensitization (lymphocyte count reduction). SAR247799 demonstrated dose-proportional increases in exposure and was eliminated with an apparent terminal half-life of 31.2-33.1 hours. Food had a small effect on the pharmacokinetics of SAR247799. SAR247799 had a low volume of distribution (7-23 L), indicating a potential to achieve dose separation for endothelial vs cardiac S1P activation pharmacology. A supratherapeutic dose (10 mg) of SAR247799 produced sustained heart rate reduction over 14 days, demonstrating cardiac S1P activation without tachyphylaxis. Sub-lymphocyte-reducing doses (≤5 mg) of SAR247799, which, based on preclinical data, are projected to activate S1P and exhibit endothelial-protective properties, had minimal-to-no heart rate reduction and displayed no marked safety findings.

Conclusion: SAR247799 is suitable for exploring the biological role of endothelial S1P activation without causing receptor desensitization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.14422DOI Listing
February 2021

A G protein-biased S1P agonist, SAR247799, protects endothelial cells without affecting lymphocyte numbers.

Sci Signal 2020 06 2;13(634). Epub 2020 Jun 2.

Diabetes and Cardiovascular Research, Sanofi US Services, 55 Corporate Drive, Bridgewater, NJ 08807, USA.

Endothelial dysfunction is a hallmark of tissue injury and is believed to initiate the development of vascular diseases. Sphingosine-1 phosphate receptor-1 (S1P) plays fundamental physiological roles in endothelial function and lymphocyte homing. Currently available clinical molecules that target this receptor are desensitizing and are essentially S1P functional antagonists that cause lymphopenia. They are clinically beneficial in autoimmune diseases such as multiple sclerosis. In patients, several side effects of S1P desensitization have been attributed to endothelial damage, suggesting that drugs with the opposite effect, namely, the ability to activate S1P could help to restore endothelial homeostasis. We found and characterized a biased agonist of S1P, SAR247799, which preferentially activated downstream G protein signaling to a greater extent than β-arrestin and internalization signaling pathways. SAR247799 activated S1P on endothelium without causing receptor desensitization and potently activated protection pathways in human endothelial cells. In a pig model of coronary endothelial damage, SAR247799 improved the microvascular hyperemic response without reducing lymphocyte numbers. Similarly, in a rat model of renal ischemia/reperfusion injury, SAR247799 preserved renal structure and function at doses that did not induce S1P-desensitizing effects, such as lymphopenia and lung vascular leakage. In contrast, a clinically used S1P functional antagonist, siponimod, conferred minimal renal protection and desensitized S1P These findings demonstrate that sustained S1P activation can occur pharmacologically without compromising the immune response, providing a new approach to treat diseases associated with endothelial dysfunction and vascular hyperpermeability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scisignal.aax8050DOI Listing
June 2020
-->