Evaluation of SSR161421, a novel orally active adenosine A3 receptor antagonist on pharmacology models

Mikus, Endre G.; Szeredi, Judit; Boer, Kinga; Timári, Géza; Finet, M.; Arányi, Péter; Galzin, Anne-Marie

doi:10.1016/j.ejphar.2012.11.049

Cited by 7 publications

(7 citation statements)

References 28 publications

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“…Recently, the selective A 3 antagonist SSR161421 has been reported to have beneficial effects in animal models of asthma (Mikus et al. ) suggesting that this off‐target activity for fostamatinib may confer a potential advantage in some inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

In vitro pharmacological profiling of R406 identifies molecular targets underlying the clinical effects of fostamatinib

Rolf

Curwen

Veldman-Jones

et al. 2015

Pharmacology Res & Perspec

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Off-target pharmacology may contribute to both adverse and beneficial effects of a new drug. In vitro pharmacological profiling is often applied early in drug discovery; there are fewer reports addressing the relevance of broad profiles to clinical adverse effects. Here, we have characterized the pharmacological profile of the active metabolite of fostamatinib, R406, linking an understanding of drug selectivity to the increase in blood pressure observed in clinical studies. R406 was profiled in a broad range of in vitro assays to generate a comprehensive pharmacological profile and key targets were further investigated using functional and cellular assay systems. A combination of traditional literature searches and text-mining approaches established potential mechanistic links between the profile of R406 and clinical side effects. R406 was selective outside the kinase domain, with only antagonist activity at the adenosine A3 receptor in the range relevant to clinical effects. R406 was less selective in the kinase domain, having activity at many protein kinases at therapeutically relevant concentrations when tested in multiple in vitro systems. Systematic literature analyses identified KDR as the probable target underlying the blood pressure increase observed in patients. While the in vitro pharmacological profile of R406 suggests a lack of selectivity among kinases, a combination of classical searching and text-mining approaches rationalized the complex profile establishing linkage between off-target pharmacology and clinically observed effects. These results demonstrate the utility of in vitro pharmacological profiling for a compound in late-stage clinical development.

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Section: Discussionmentioning

confidence: 99%

In vitro pharmacological profiling of R406 identifies molecular targets underlying the clinical effects of fostamatinib

Rolf

Curwen

Veldman-Jones

et al. 2015

Pharmacology Res & Perspec

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“…Within 24 h, BALB/c mice were intravenously injected with 5 × 10 6 T cell-depleted BM cells and 2 × 10 6 T cells from C57BL/6 mice 10,11 . Mice were given medicated water (25 μg/ml neomycin/0.3 U/ml polymyxin B; Sigma-Aldrich) 12–16 . The survival of mice was monitored daily, and body weight was measured weekly.…”

Section: Methodsmentioning

confidence: 99%

Reduction in murine acute GVHD severity by human gingival tissue-derived mesenchymal stem cells via the CD39 pathways

Xia

Zhou

et al. 2019

Cell Death Dis

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Human gingival tissue-derived mesenchymal stem cells (GMSCs) present an accessible source of mesenchymal stem cells (MSCs) for treating autoimmune diseases. Here we show that human GMSCs can prevent and treat acute graft-versus-host disease (GVHD) in two different mouse models. Our results indicate that besides exhibiting suppressive function in vitro and in vivo, GMSCs may also regulate the conversion of Tregs to Th1 and/or Th17-like cells, as well as stabilize Foxp3 expression. Furthermore, GMSC-mediated prevention of acute GVHD was dependent on CD39 signaling that play an important role in the function and stability of Tregs. Finally, we also observed stronger protective ability of GMSCs with greater expansion ability compared with BMSCs or ASCs. These results indicate that human GMSCs have the potential to be used to treat GVHD.

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“…For comparison, mean plasma C max values were 49, 73 and 97 μg/mL in the rats orally dosed with 200, 500 and 750 mg/kg of DSM421, respectively. Adenosine A 3 receptor ligands, among their other effects, have been associated with inflammatory responses including bronchoconstriction/relaxation (Fishman et al, 2012;Mikus et al, 2013). Specifically, activation of the adenosine A 3 receptor can result in increased bronchoconstriction (Mikus et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Adenosine A 3 receptor ligands, among their other effects, have been associated with inflammatory responses including bronchoconstriction/relaxation (Fishman et al, 2012;Mikus et al, 2013). Specifically, activation of the adenosine A 3 receptor can result in increased bronchoconstriction (Mikus et al, 2013). Bronchoconstriction produces changes to the normal respiratory pattern, and those changes can vary both in terms of their severity and direction with various respiratory parameters, potentially due to differences in the species and/or bronchoconstrictor tested (Authier et al, 2009;Harris et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Increased stress associated with head-out plethysmography testing can exacerbate respiratory effects and lead to mortality in rats

Lynch

Rossignol

Moehrle

et al. 2019

Journal of Pharmacological and Toxicological Methods

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Introduction: DSM421, a dihydroorotate dehydrogenase inhibitor, was in preclinical development as a potential treatment option for malaria. When tested in a core battery of safety pharmacology assays, DSM421 did not produce any effects at oral doses up to 750 mg/kg in an Irwin test in rats, but a respiratory study in rats using head-out plethysmography resulted in substantial changes in respiratory function as well as moribundity and mortality at that and lower doses. An investigation was performed to determine the source of this discrepancy. Methods: Potential testing errors, differences in types of plethysmography testing chambers, effects on stress indicators, and off-target activity were investigated. Results: Respiratory changes and toxicity (resulting in euthanasia in extremis) were confirmed in a repeat, head-out plethysmography test, but the effects of DSM421 were much less severe overall when the rats were tested in whole-body chambers. Additionally, at the end of the 5-hour postdosing respiratory monitoring periods, levels of stress-related hormones (particularly corticosterone) were higher overall in the head-out, than in the whole-body, tested rats. Furthermore, DSM421 was found to produce changes in cardiovascular function in unrestrained rats, and it was shown to have off-target binding affinity at the adenosine A 3 receptor (which is associated with bronchoconstriction). Discussion: The generalized stress inherent to head-out plethysmography testing exacerbated the respiratory effects of DSM421 and was possibly compounded by DSM421's cardiovascular *

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Evaluation of SSR161421, a novel orally active adenosine A3 receptor antagonist on pharmacology models

Cited by 7 publications

References 28 publications

In vitro pharmacological profiling of R406 identifies molecular targets underlying the clinical effects of fostamatinib

In vitro pharmacological profiling of R406 identifies molecular targets underlying the clinical effects of fostamatinib

Reduction in murine acute GVHD severity by human gingival tissue-derived mesenchymal stem cells via the CD39 pathways

Increased stress associated with head-out plethysmography testing can exacerbate respiratory effects and lead to mortality in rats

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