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Kenneth A Jacobson - One of the best experts on this subject based on the ideXlab platform.
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Design and in vivo activity of A_3 Adenosine Receptor Agonist prodrugs
Purinergic Signalling, 2020Co-Authors: R. Rama Suresh, Dilip K Tosh, Shanu Jain, Zhoumou Chen, Yanling Ma, Maren C. Podszun, Yaron Rotman, Daniela Salvemini, Kenneth A JacobsonAbstract:Prodrugs (MRS7422, MRS7476) of highly selective A_3 Adenosine Receptor (AR) Agonists Cl-IB-MECA and MRS5698, respectively, were synthesized by succinylation of the 2′ and 3′ hydroxyl groups, and the parent, active drug was shown to be readily liberated upon incubation with liver esterases. The prodrug MRS7476 had greatly increased aqueous solubility compared with parent MRS5698 and was fully efficacious and with a longer duration than MRS7422 in reversing mouse neuropathic pain (chronic constriction injury model, 3 μmol/kg, p.o.), a known A_3AR effect. MRS7476 (5 mg/kg, p.o., twice daily) was found to protect against non-alcoholic steatohepatitis (NASH) in the STAM mouse model, indicated by the NAFLD activity score. Hepatocyte ballooning, IL-10 production, and liver histology were significantly normalized in the MRS7476-treated mice, but not liver fibrosis (no change in ACTA2 levels) or inflammation. Hepatic expression of ADORA3 in human NAFLD patients was 1.9-fold lower compared to normal controls. Adora3 expression determined by qPCR in primary mouse liver was associated with the stellate cells, and its mouse full body A_3AR knockout worsened liver markers of inflammation and steatosis. Thus, we have introduced a reversible prodrug strategy that enables water solubility and in vivo activity of masked A_3AR Agonists in models of two disease conditions.
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design and in vivo activity of a3 Adenosine Receptor Agonist prodrugs
Purinergic Signalling, 2020Co-Authors: R. Rama Suresh, Dilip K Tosh, Shanu Jain, Zhoumou Chen, Maren C. Podszun, Yaron Rotman, Daniela Salvemini, Kenneth A JacobsonAbstract:Prodrugs (MRS7422, MRS7476) of highly selective A3 Adenosine Receptor (AR) Agonists Cl-IB-MECA and MRS5698, respectively, were synthesized by succinylation of the 2' and 3' hydroxyl groups, and the parent, active drug was shown to be readily liberated upon incubation with liver esterases. The prodrug MRS7476 had greatly increased aqueous solubility compared with parent MRS5698 and was fully efficacious and with a longer duration than MRS7422 in reversing mouse neuropathic pain (chronic constriction injury model, 3 μmol/kg, p.o.), a known A3AR effect. MRS7476 (5 mg/kg, p.o., twice daily) was found to protect against non-alcoholic steatohepatitis (NASH) in the STAM mouse model, indicated by the NAFLD activity score. Hepatocyte ballooning, IL-10 production, and liver histology were significantly normalized in the MRS7476-treated mice, but not liver fibrosis (no change in ACTA2 levels) or inflammation. Hepatic expression of ADORA3 in human NAFLD patients was 1.9-fold lower compared to normal controls. Adora3 expression determined by qPCR in primary mouse liver was associated with the stellate cells, and its mouse full body A3AR knockout worsened liver markers of inflammation and steatosis. Thus, we have introduced a reversible prodrug strategy that enables water solubility and in vivo activity of masked A3AR Agonists in models of two disease conditions.
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metabolic mapping of a3 Adenosine Receptor Agonist mrs5980
Biochemical Pharmacology, 2015Co-Authors: Zhongze Fang, Dilip K Tosh, Naoki Tanaka, Haina Wang, Kristopher W Krausz, Robert D Oconnor, Kenneth A Jacobson, Frank J GonzalezAbstract:ABSTRACT (1 S ,2 R ,3 S ,4 R ,5 S )-4-(2-((5-Chlorothiophen-2-yl)ethynyl)-6-(methylamino)-9 H -purin-9-yl)-2,3-dihydroxy- N -methylbicyclo[3.1.0]hexane-1-carboxamide ( MRS5980) is an A 3 AR selective Agonist containing multiple Receptor affinity- and selectivity-enhancing modifications and a therapeutic candidate drug for many inflammatory diseases. Metabolism-related poor pharmacokinetic behavior and toxicities are a major reason for drug R&D failure. Metabolomics with UPLC–MS was employed to profile the metabolism of MRS5980 and MRS5980-induced disruption of endogenous compounds. Recombinant drug-metabolizing enzymes screening experiment were used to determine the enzymes involved in MRS5980 metabolism. Analysis of lipid metabolism-related genes was performed to investigate the reason for MRS5980-induced lipid metabolic disorders. Unsupervised principal components analysis separated the control and MRS5980 treatment groups in feces, urine, and liver samples, but not in bile and serum. The major ions mainly contributing to the separation of feces and urine were oxidized MRS5980, glutathione (GSH) conjugates and cysteine conjugate (degradation product of the GSH conjugates) of MRS5980. The major ions contributing to the group separation of liver samples were phosphatidylcholines. In vitro incubation experiments showed the involvement of CYP3A enzymes in the oxidative metabolism of MRS5980 and direct GSH reactivity of MRS5980. The electrophilic attack by MRS5980 is a minor pathway and did not alter GSH levels in liver or liver histology, and thus may be of minor clinical consequence. Gene expression analysis further showed decreased expression of PC biosynthetic genes choline kinase a and b, which further accelerated conversion of lysophosphatidylcholine to phosphatidylcholines through increasing the expression of lysophosphatidylcholine acyltransferase 3. These data will be useful to guide rational design of drugs targeting A 3 AR, considering efficacy, metabolic elimination, and electrophilic reactivity.
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Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A_3 Adenosine Receptor Agonist that protects against chronic neuropathic pain
Purinergic Signalling, 2015Co-Authors: Dilip K Tosh, Daniela Salvemini, Janak Padia, Kenneth A JacobsonAbstract:We reported that 2-(3,4-difluorophenylethynyl)- N ^6-3-chlorobenzyl ( N )-methanocarba Adenosine derivative 1 (MRS5698) binds selectively to human and mouse A_3 Adenosine Receptors (A_3ARs, K _ i 3 nM). It is becoming an important pharmacological tool for defining A_3AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from d -ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at
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efficient large scale synthesis and preclinical studies of mrs5698 a highly selective a3 Adenosine Receptor Agonist that protects against chronic neuropathic pain
Purinergic Signalling, 2015Co-Authors: Dilip K Tosh, Daniela Salvemini, Janak Padia, Kenneth A JacobsonAbstract:We reported that 2-(3,4-difluorophenylethynyl)-N 6-3-chlorobenzyl (N)-methanocarba Adenosine derivative 1 (MRS5698) binds selectively to human and mouse A3 Adenosine Receptors (A3ARs, K i 3 nM). It is becoming an important pharmacological tool for defining A3AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from d-ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at <10 μM, and was largely bound to plasma proteins. It was well tolerated in the rat at doses of ≤200 mg/kg i.p. A 1 mg/kg i.p. dose in the mouse displayed t 1/2 of 1.09 h and plasma Cmax of 204 nM at 1 h with an AUC of 213 ng × h/mL. CACO-2 bidirectional transport studies suggested intestinal efflux of MRS5698 (efflux ratio 86). Although the oral %F is only 5 %, the beneficial effect to reverse pain lasted for at least 2 h in the CCI model in rats, using the same vehicle for oral administration of a high dose. The stability, low toxicity, lack of CYP interaction, pharmacokinetic half-life, and in vivo efficacy suggest that MRS5698 is a preferred compound for further consideration as a treatment for neuropathic pain.
Luiz Belardinelli - One of the best experts on this subject based on the ideXlab platform.
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effects of Adenosine and a selective a2a Adenosine Receptor Agonist on hemodynamic and thallium 201 and technetium 99m sestamibi biodistribution and kinetics
Jacc-cardiovascular Imaging, 2009Co-Authors: Choukri Mekkaoui, Luiz Belardinelli, Farid Jadbabaie, Donald P Dione, David F Meoli, Kailasnath Purushothaman, Albert J SinusasAbstract:Objectives The purpose of this study was to compare a selective A2A Adenosine Receptor Agonist (regadenoson) with Adenosine in clinically relevant canine models with regard to effects on hemodynamics and thallium-201 (201Tl) and technetium-99m (99mTc)-sestaMIBI biodistribution and kinetics. Background The clinical application of vasodilator stress for perfusion imaging requires consideration of the effects of these vasodilating agents on systemic hemodynamics, coronary flow, and radiotracer uptake and clearance kinetics. Methods Sequential imaging and arterial blood sampling was performed on control, anesthetized closed-chest canines (n = 7) to evaluate radiotracer biodistribution and kinetics after either a bolus administration of regadenoson (2.5 μg/kg) or 4.5-min infusion of Adenosine (280 μg/kg). The effects of regadenoson on coronary flow and myocardial radiotracer uptake were then evaluated in an open-chest canine model of a critical stenosis (n = 7). Results from ex vivo single-photon emission computed tomography were compared with tissue well-counting. Results The use of regadenoson compared favorably with Adenosine in regard to the duration and magnitude of the hemodynamic effects and the effect on 201Tl and 99mTc-sestaMIBI biodistribution and kinetics. The arterial blood clearance half-time was significantly faster for 99mTc-sestaMIBI (regadenoson: 1.4 ± 0.03 min; Adenosine: 1.5 ± 0.08 min) than for 201Tl (regadenoson: 2.5 ± 0.16 min, p Conclusions The bolus administration of regadenoson produced a hyperemic response comparable to a standard infusion of Adenosine. The biodistribution and clearance of both 201Tl and 99mTc-sestaMIBI during regadenoson were similar to Adenosine vasodilation. Ex vivo perfusion images under the most ideal conditions permitted detection of a critical stenosis, although 201Tl offered significant advantages over 99mTc-sestaMIBI for perfusion imaging during regadenoson vasodilator stress.
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regadenoson a selective a2a Adenosine Receptor Agonist causes dose dependent increases in coronary blood flow velocity in humans
Journal of Nuclear Cardiology, 2007Co-Authors: Hsiao D Lieu, John C Shryock, Gregory O Von Mering, Toufigh Gordi, Brent Blackburn, Ann Olmsted, Luiz Belardinelli, Richard A KerenskyAbstract:Background Regadenoson is a selective A2A Adenosine Receptor Agonist and vasodilator used to increase the heterogeneity of distribution of coronary blood flow during myocardial perfusion imaging. This study characterized the dose dependence of regadenoson-induced coronary hyperemia.
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antilipolytic activity of a novel partial a1 Adenosine Receptor Agonist devoid of cardiovascular effects comparison with nicotinic acid
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Arvinder Dhalla, John C Shryock, Melissa Santikul, Michelle Smith, Meiyee Wong, Luiz BelardinelliAbstract:Elevated lipolysis and circulating free fatty acid (FFA) levels have been linked to the pathogenesis of insulin resistance. A 1 Adenosine Receptor Agonists are potent inhibitors of lipolysis. Several A 1 Agonists have been tested as potential antilipolytic agents; however, their effect on the cardiovascular system remains a potential problem for development of these agents as drugs. In the present study, we report that CVT-3619 [(2-{6-[((1 R ,2 R )-2-hydroxycyclopentyl) amino] purin9-yl} (4 S ,5 S ,2 R ,3 R )5-[(2fluorophenylthio) methyl] oxolane-3,4-diol)], a novel partial A 1 Receptor Agonist, significantly reduces circulating FFA levels without any effect on heart rate and blood pressure in awake rats. Rats were implanted with indwelling arterial and venous cannulas to obtain serial blood samples, record arterial pressure, and administer drug. CVT-3619 decreased FFA levels in a dose-dependent manner at doses from 1 up to 10 mg/kg. The FFA-lowering effect was blocked by the A 1 Receptor antAgonist, 1,3-dipropyl-8-cyclopentylxanthine. Triglyceride (TG) levels were also significantly reduced by CVT-3619 treatment in the absence and presence of Triton. Tachyphylaxis of the antilipolytic effect of CVT-3619 (1 mg/kg i.v. bolus) was not observed with three consecutive treatments. An acute reduction of FFA by CVT-3619 was not followed by a rebound increase of FFA as seen with nicotinic acid. The potency of insulin to decrease lipolysis was increased 4-fold ( p 1 Agonist that lowers circulating FFA and TG levels by inhibiting lipolysis. CVT-3619 has antilipolytic effects at doses that do not elicit cardiovascular effects.
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selective a2a Adenosine Receptor Agonist as a coronary vasodilator in conscious dogs potential for use in myocardial perfusion imaging
Journal of Cardiovascular Pharmacology, 2003Co-Authors: Jeannoel Trochu, Luiz Belardinelli, Gong Zhao, Heiner Post, Xiaobin Xu, Francis L Belloni, Thomas H HintzeAbstract:: The authors sought to demonstrate the advantages of a selective, potent, short-acting A Adenosine Receptor Agonist, CVT-3146 (2-(N-pyrazolyl)Ado derivative), for potential clinical use as a coronary vasodilator during myocardial perfusion imaging. The use of Adenosine in a pharmacological stress test during myocardial imaging is limited by side effects mediated by A1 and A2B Adenosine Receptors and by its ultrashort duration of action. CVT-3146 (0.1-5 microg/kg) and Adenosine (13-267 microg/kg) were given as peripheral intravenous injections in 10 awake dogs instrumented for measurement of coronary blood flow (CBF). CVT-3146 caused a dose-dependent increase of CBF (ED50 = 0.34 +/- 0.08 microg/kg, maximal increase = 221 +/- 18%, n = 6). Adenosine was less potent (ED = 51 +/- 15 microg/kg, p < 0.05) but equieffective (maximal increase in CBF = 227 +/- 11%). The increase in CBF caused by 2.5 microg/kg CVT-3146 reached 84 +/- 5% of the maximal reactive hyperemia following 20 s of coronary occlusion (n = 4). After a 10-s injection of CVT-3146 (2.5 microg/kg), the increase in CBF remained at least twofold above baseline for 97 +/- 14 s, whereas for Adenosine (267 microg/kg), the twofold increase in CBF lasted only 24 +/- 2 s (p < 0.01, n = 6). A 30-s injection of 2.5 microg/kg CVT-3146 prolonged the twofold increase in CBF up to 221 +/- 20 s. No atrioventricular block was noted. At 2.5 microg/kg, the peak effect of CVT-3146 on CBF was associated with a short-lasting (20 +/- 6 s) increase in heart rate (78 +/- 9 bpm) and decrease in mean arterial blood pressure (13 +/- 6 mm Hg, p < 0.05, n = 6). CVT-3146 is a potent coronary vasodilator. Its short duration of action, minimal and transient systemic hemodynamic effects, and ease of administration may make this Agonist suitable for pharmacological coronary vasodilation during myocardial perfusion imaging for noninvasive detection of subcritical arterial stenosis.
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a comparison of an a1 Adenosine Receptor Agonist cvt 510 with diltiazem for slowing of av nodal conduction in guinea pig
British Journal of Pharmacology, 1999Co-Authors: Stephen Snowdy, Brent Blackburn, Hui Xiu Liang, Marek G Nelson, Lisa Wang, Jurg R Pfister, Bhavender P Sharma, Andrew A Wolff, Luiz BelardinelliAbstract:The purpose of this study was to compare the pharmacological properties (i.e. the AV nodal depressant, vasodilator, and inotropic effects) of two AV nodal blocking agents belonging to different drug classes; a novel A1 Adenosine Receptor (A1 Receptor) Agonist, N-(3(R)-tetrahydrofuranyl)-6-aminopurine riboside (CVT-510), and the prototypical calcium channel blocker diltiazem. In the atrial-paced isolated heart, CVT-510 was approximately 5 fold more potent to prolong the stimulus-to-His bundle (S–H interval), a measure of slowing AV nodal conduction (EC50=41 nM) than to increase coronary conductance (EC50=200 nM). At concentrations of CVT-510 (40 nM) and diltiazem (1 μM) that caused equal prolongation of S–H interval (∼10 ms), diltiazem, but not CVT-510, significantly reduced left ventricular developed pressure (LVP) and markedly increased coronary conductance. CVT-510 shortened atrial (EC50=73 nM) but not the ventricular monophasic action potentials (MAP). In atrial-paced anaesthetized guinea-pigs, intravenous infusions of CVT-510 and diltiazem caused nearly equal prolongations of P–R interval. However, diltiazem, but not CVT-510, significantly reduced mean arterial blood pressure. Both CVT-510 and diltiazem prolonged S–H interval, i.e., slowed AV nodal conduction. However, the A1 Receptor-selective Agonist CVT-510 did so without causing the negative inotropic, vasodilator, and hypotensive effects associated with diltiazem. Because CVT-510 did not affect the ventricular action potential, it is unlikely that this Agonist will have a proarrythmic action in ventricular myocardium. British Journal of Pharmacology (1999) 126, 137–146; doi:10.1038/sj.bjp.0702287
Henry J Kaplan - One of the best experts on this subject based on the ideXlab platform.
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an a2b Adenosine Receptor Agonist promotes th17 autoimmune responses in experimental autoimmune uveitis eau via dendritic cell activation
PLOS ONE, 2015Co-Authors: Mingjiazi Chen, Dongchun Liang, Hui Shao, Henry J KaplanAbstract:We have recently reported that, although Adenosine Receptor (AR) Agonists have a suppressive effect on Th1 autoreactive T cells, their effect on Th17 autoreactive T cells and γδ T cells is stimulatory and this effect is mainly mediated via A2A Adenosine Receptors (A2ARs). In this study, we further demonstrate that treatment of C57BL/6 (B6) mice with a selective A2B Adenosine Receptor (A2BR) Agonist greatly enhanced the development of experimental autoimmune uveitis (EAU), whereas treatment with an A2BR antAgonist significantly ameliorated severity of EAU. The A2BR Agonist-treated mice showed augmented Th17, but not Th1, responses. Mechanistic studies showed that the A2BR Agonist-induced enhancement of the Th17 response was significantly lower when TCR-δ-/- mice received the same treatment and that transfer of γδ T cells into TCR-δ-/- mice partially restored this effect. We also showed that dendritic cells (DCs) from A2BR Agonist-treated mice showed a significantly increased ability to activate γδ T cells and Th17 autoreactive T cells. Thus, our previous studies have shown that, in EAU, activated γδ T cells possess greatly increased ability to enhance Th17 autoimmune responses. In the present study, we showed that exposure of DCs to A2BR Agonist facilitated γδ T cell activation, leading to augmented Th17 responses and progressive EAU development. Our results further support our previous finding that AR Agonists have distinct effects on Th1 and Th17 autoimmune responses.
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anti inflammatory or proinflammatory effect of an Adenosine Receptor Agonist on the th17 autoimmune response is inflammatory environment dependent
Journal of Immunology, 2014Co-Authors: Dongchun Liang, Mingjiazi Chen, Hui Shao, Henry J KaplanAbstract:Adenosine is a key endogenous signaling molecule that regulates a wide range of physiological functions, including immune system function and inflammation. Studies have shown that Adenosine Receptor (AR) Agonists can be either anti-inflammatory or proinflammatory in immune responses and in inflammation, and the clarification of the mechanisms causing these opposing effects should provide a better guide for therapeutic intervention. Whereas previous studies mostly examined the effects of AR Agonists on Th1-type immune responses, in this study, we compared their effect on Th17 and Th1 autoimmune responses in experimental autoimmune uveitis, a mouse model of human uveitis induced by immunization with the human interphotoReceptor retinoid-binding protein peptides 1–20. We showed that injection of mice with a nonselective AR Agonist, 5′- N -ethylcarboxamidoAdenosine (NECA), at an early stage after immunization had an inhibitory effect on both Th1 and Th17 responses, whereas injection of the same amount of NECA at a late stage inhibited the Th1 response but had an enhancing effect on the Th17 response. We also showed that the effects of NECA on Th1 and Th17 responses were completely dissociated, that the enhancing effect of NECA on Th17 responses was modulated by γδ T cells, and that the response of γδ T cells to NECA was determined by their activation status. We conclude that the inflammatory environment has a strong impact on converting the effect of AR Agonist on the Th17 autoimmune response from anti-inflammatory to proinflammatory. Our observation should help in the designing of better AR-targeted therapies.
Dilip K Tosh - One of the best experts on this subject based on the ideXlab platform.
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Design and in vivo activity of A_3 Adenosine Receptor Agonist prodrugs
Purinergic Signalling, 2020Co-Authors: R. Rama Suresh, Dilip K Tosh, Shanu Jain, Zhoumou Chen, Yanling Ma, Maren C. Podszun, Yaron Rotman, Daniela Salvemini, Kenneth A JacobsonAbstract:Prodrugs (MRS7422, MRS7476) of highly selective A_3 Adenosine Receptor (AR) Agonists Cl-IB-MECA and MRS5698, respectively, were synthesized by succinylation of the 2′ and 3′ hydroxyl groups, and the parent, active drug was shown to be readily liberated upon incubation with liver esterases. The prodrug MRS7476 had greatly increased aqueous solubility compared with parent MRS5698 and was fully efficacious and with a longer duration than MRS7422 in reversing mouse neuropathic pain (chronic constriction injury model, 3 μmol/kg, p.o.), a known A_3AR effect. MRS7476 (5 mg/kg, p.o., twice daily) was found to protect against non-alcoholic steatohepatitis (NASH) in the STAM mouse model, indicated by the NAFLD activity score. Hepatocyte ballooning, IL-10 production, and liver histology were significantly normalized in the MRS7476-treated mice, but not liver fibrosis (no change in ACTA2 levels) or inflammation. Hepatic expression of ADORA3 in human NAFLD patients was 1.9-fold lower compared to normal controls. Adora3 expression determined by qPCR in primary mouse liver was associated with the stellate cells, and its mouse full body A_3AR knockout worsened liver markers of inflammation and steatosis. Thus, we have introduced a reversible prodrug strategy that enables water solubility and in vivo activity of masked A_3AR Agonists in models of two disease conditions.
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design and in vivo activity of a3 Adenosine Receptor Agonist prodrugs
Purinergic Signalling, 2020Co-Authors: R. Rama Suresh, Dilip K Tosh, Shanu Jain, Zhoumou Chen, Maren C. Podszun, Yaron Rotman, Daniela Salvemini, Kenneth A JacobsonAbstract:Prodrugs (MRS7422, MRS7476) of highly selective A3 Adenosine Receptor (AR) Agonists Cl-IB-MECA and MRS5698, respectively, were synthesized by succinylation of the 2' and 3' hydroxyl groups, and the parent, active drug was shown to be readily liberated upon incubation with liver esterases. The prodrug MRS7476 had greatly increased aqueous solubility compared with parent MRS5698 and was fully efficacious and with a longer duration than MRS7422 in reversing mouse neuropathic pain (chronic constriction injury model, 3 μmol/kg, p.o.), a known A3AR effect. MRS7476 (5 mg/kg, p.o., twice daily) was found to protect against non-alcoholic steatohepatitis (NASH) in the STAM mouse model, indicated by the NAFLD activity score. Hepatocyte ballooning, IL-10 production, and liver histology were significantly normalized in the MRS7476-treated mice, but not liver fibrosis (no change in ACTA2 levels) or inflammation. Hepatic expression of ADORA3 in human NAFLD patients was 1.9-fold lower compared to normal controls. Adora3 expression determined by qPCR in primary mouse liver was associated with the stellate cells, and its mouse full body A3AR knockout worsened liver markers of inflammation and steatosis. Thus, we have introduced a reversible prodrug strategy that enables water solubility and in vivo activity of masked A3AR Agonists in models of two disease conditions.
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metabolic mapping of a3 Adenosine Receptor Agonist mrs5980
Biochemical Pharmacology, 2015Co-Authors: Zhongze Fang, Dilip K Tosh, Naoki Tanaka, Haina Wang, Kristopher W Krausz, Robert D Oconnor, Kenneth A Jacobson, Frank J GonzalezAbstract:ABSTRACT (1 S ,2 R ,3 S ,4 R ,5 S )-4-(2-((5-Chlorothiophen-2-yl)ethynyl)-6-(methylamino)-9 H -purin-9-yl)-2,3-dihydroxy- N -methylbicyclo[3.1.0]hexane-1-carboxamide ( MRS5980) is an A 3 AR selective Agonist containing multiple Receptor affinity- and selectivity-enhancing modifications and a therapeutic candidate drug for many inflammatory diseases. Metabolism-related poor pharmacokinetic behavior and toxicities are a major reason for drug R&D failure. Metabolomics with UPLC–MS was employed to profile the metabolism of MRS5980 and MRS5980-induced disruption of endogenous compounds. Recombinant drug-metabolizing enzymes screening experiment were used to determine the enzymes involved in MRS5980 metabolism. Analysis of lipid metabolism-related genes was performed to investigate the reason for MRS5980-induced lipid metabolic disorders. Unsupervised principal components analysis separated the control and MRS5980 treatment groups in feces, urine, and liver samples, but not in bile and serum. The major ions mainly contributing to the separation of feces and urine were oxidized MRS5980, glutathione (GSH) conjugates and cysteine conjugate (degradation product of the GSH conjugates) of MRS5980. The major ions contributing to the group separation of liver samples were phosphatidylcholines. In vitro incubation experiments showed the involvement of CYP3A enzymes in the oxidative metabolism of MRS5980 and direct GSH reactivity of MRS5980. The electrophilic attack by MRS5980 is a minor pathway and did not alter GSH levels in liver or liver histology, and thus may be of minor clinical consequence. Gene expression analysis further showed decreased expression of PC biosynthetic genes choline kinase a and b, which further accelerated conversion of lysophosphatidylcholine to phosphatidylcholines through increasing the expression of lysophosphatidylcholine acyltransferase 3. These data will be useful to guide rational design of drugs targeting A 3 AR, considering efficacy, metabolic elimination, and electrophilic reactivity.
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Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A_3 Adenosine Receptor Agonist that protects against chronic neuropathic pain
Purinergic Signalling, 2015Co-Authors: Dilip K Tosh, Daniela Salvemini, Janak Padia, Kenneth A JacobsonAbstract:We reported that 2-(3,4-difluorophenylethynyl)- N ^6-3-chlorobenzyl ( N )-methanocarba Adenosine derivative 1 (MRS5698) binds selectively to human and mouse A_3 Adenosine Receptors (A_3ARs, K _ i 3 nM). It is becoming an important pharmacological tool for defining A_3AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from d -ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at
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efficient large scale synthesis and preclinical studies of mrs5698 a highly selective a3 Adenosine Receptor Agonist that protects against chronic neuropathic pain
Purinergic Signalling, 2015Co-Authors: Dilip K Tosh, Daniela Salvemini, Janak Padia, Kenneth A JacobsonAbstract:We reported that 2-(3,4-difluorophenylethynyl)-N 6-3-chlorobenzyl (N)-methanocarba Adenosine derivative 1 (MRS5698) binds selectively to human and mouse A3 Adenosine Receptors (A3ARs, K i 3 nM). It is becoming an important pharmacological tool for defining A3AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from d-ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at <10 μM, and was largely bound to plasma proteins. It was well tolerated in the rat at doses of ≤200 mg/kg i.p. A 1 mg/kg i.p. dose in the mouse displayed t 1/2 of 1.09 h and plasma Cmax of 204 nM at 1 h with an AUC of 213 ng × h/mL. CACO-2 bidirectional transport studies suggested intestinal efflux of MRS5698 (efflux ratio 86). Although the oral %F is only 5 %, the beneficial effect to reverse pain lasted for at least 2 h in the CCI model in rats, using the same vehicle for oral administration of a high dose. The stability, low toxicity, lack of CYP interaction, pharmacokinetic half-life, and in vivo efficacy suggest that MRS5698 is a preferred compound for further consideration as a treatment for neuropathic pain.
Daniela Salvemini - One of the best experts on this subject based on the ideXlab platform.
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Design and in vivo activity of A_3 Adenosine Receptor Agonist prodrugs
Purinergic Signalling, 2020Co-Authors: R. Rama Suresh, Dilip K Tosh, Shanu Jain, Zhoumou Chen, Yanling Ma, Maren C. Podszun, Yaron Rotman, Daniela Salvemini, Kenneth A JacobsonAbstract:Prodrugs (MRS7422, MRS7476) of highly selective A_3 Adenosine Receptor (AR) Agonists Cl-IB-MECA and MRS5698, respectively, were synthesized by succinylation of the 2′ and 3′ hydroxyl groups, and the parent, active drug was shown to be readily liberated upon incubation with liver esterases. The prodrug MRS7476 had greatly increased aqueous solubility compared with parent MRS5698 and was fully efficacious and with a longer duration than MRS7422 in reversing mouse neuropathic pain (chronic constriction injury model, 3 μmol/kg, p.o.), a known A_3AR effect. MRS7476 (5 mg/kg, p.o., twice daily) was found to protect against non-alcoholic steatohepatitis (NASH) in the STAM mouse model, indicated by the NAFLD activity score. Hepatocyte ballooning, IL-10 production, and liver histology were significantly normalized in the MRS7476-treated mice, but not liver fibrosis (no change in ACTA2 levels) or inflammation. Hepatic expression of ADORA3 in human NAFLD patients was 1.9-fold lower compared to normal controls. Adora3 expression determined by qPCR in primary mouse liver was associated with the stellate cells, and its mouse full body A_3AR knockout worsened liver markers of inflammation and steatosis. Thus, we have introduced a reversible prodrug strategy that enables water solubility and in vivo activity of masked A_3AR Agonists in models of two disease conditions.
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design and in vivo activity of a3 Adenosine Receptor Agonist prodrugs
Purinergic Signalling, 2020Co-Authors: R. Rama Suresh, Dilip K Tosh, Shanu Jain, Zhoumou Chen, Maren C. Podszun, Yaron Rotman, Daniela Salvemini, Kenneth A JacobsonAbstract:Prodrugs (MRS7422, MRS7476) of highly selective A3 Adenosine Receptor (AR) Agonists Cl-IB-MECA and MRS5698, respectively, were synthesized by succinylation of the 2' and 3' hydroxyl groups, and the parent, active drug was shown to be readily liberated upon incubation with liver esterases. The prodrug MRS7476 had greatly increased aqueous solubility compared with parent MRS5698 and was fully efficacious and with a longer duration than MRS7422 in reversing mouse neuropathic pain (chronic constriction injury model, 3 μmol/kg, p.o.), a known A3AR effect. MRS7476 (5 mg/kg, p.o., twice daily) was found to protect against non-alcoholic steatohepatitis (NASH) in the STAM mouse model, indicated by the NAFLD activity score. Hepatocyte ballooning, IL-10 production, and liver histology were significantly normalized in the MRS7476-treated mice, but not liver fibrosis (no change in ACTA2 levels) or inflammation. Hepatic expression of ADORA3 in human NAFLD patients was 1.9-fold lower compared to normal controls. Adora3 expression determined by qPCR in primary mouse liver was associated with the stellate cells, and its mouse full body A3AR knockout worsened liver markers of inflammation and steatosis. Thus, we have introduced a reversible prodrug strategy that enables water solubility and in vivo activity of masked A3AR Agonists in models of two disease conditions.
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Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A_3 Adenosine Receptor Agonist that protects against chronic neuropathic pain
Purinergic Signalling, 2015Co-Authors: Dilip K Tosh, Daniela Salvemini, Janak Padia, Kenneth A JacobsonAbstract:We reported that 2-(3,4-difluorophenylethynyl)- N ^6-3-chlorobenzyl ( N )-methanocarba Adenosine derivative 1 (MRS5698) binds selectively to human and mouse A_3 Adenosine Receptors (A_3ARs, K _ i 3 nM). It is becoming an important pharmacological tool for defining A_3AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from d -ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at
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efficient large scale synthesis and preclinical studies of mrs5698 a highly selective a3 Adenosine Receptor Agonist that protects against chronic neuropathic pain
Purinergic Signalling, 2015Co-Authors: Dilip K Tosh, Daniela Salvemini, Janak Padia, Kenneth A JacobsonAbstract:We reported that 2-(3,4-difluorophenylethynyl)-N 6-3-chlorobenzyl (N)-methanocarba Adenosine derivative 1 (MRS5698) binds selectively to human and mouse A3 Adenosine Receptors (A3ARs, K i 3 nM). It is becoming an important pharmacological tool for defining A3AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from d-ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at <10 μM, and was largely bound to plasma proteins. It was well tolerated in the rat at doses of ≤200 mg/kg i.p. A 1 mg/kg i.p. dose in the mouse displayed t 1/2 of 1.09 h and plasma Cmax of 204 nM at 1 h with an AUC of 213 ng × h/mL. CACO-2 bidirectional transport studies suggested intestinal efflux of MRS5698 (efflux ratio 86). Although the oral %F is only 5 %, the beneficial effect to reverse pain lasted for at least 2 h in the CCI model in rats, using the same vehicle for oral administration of a high dose. The stability, low toxicity, lack of CYP interaction, pharmacokinetic half-life, and in vivo efficacy suggest that MRS5698 is a preferred compound for further consideration as a treatment for neuropathic pain.
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a3 Adenosine Receptor Agonist prevents the development of paclitaxel induced neuropathic pain by modulating spinal glial restricted redox dependent signaling pathways
Pain, 2014Co-Authors: Kali Janes, Dilip K Tosh, Kenneth A Jacobson, Emanuela Esposito, Timothy M Doyle, Salvatore Cuzzocrea, Daniela SalveminiAbstract:Abstract Chemotherapy-induced peripheral neuropathy accompanied by chronic neuropathic pain is the major dose-limiting toxicity of several anticancer agents including the taxane paclitaxel (Taxol). A critical mechanism underlying paclitaxel-induced neuropathic pain is the increased production of peroxynitrite in spinal cord generated in response to activation of the superoxide-generating enzyme, NADPH oxidase. Peroxynitrite in turn contributes to the development of neuropathic pain by modulating several redox-dependent events in spinal cord. We recently reported that activation of the Gi/Gq-coupled A3 Adenosine Receptor (A3AR) with selective A3AR Agonists (ie, IB-MECA) blocked the development of chemotherapy induced-neuropathic pain evoked by distinct agents, including paclitaxel, without interfering with anticancer effects. The mechanism or mechanisms of action underlying these beneficial effects has yet to be explored. We now demonstrate that IB-MECA attenuates the development of paclitaxel-induced neuropathic pain by inhibiting the activation of spinal NADPH oxidase and two downstream redox-dependent systems. The first relies on inhibition of the redox-sensitive transcription factor (NFκB) and mitogen activated protein kinases (ERK and p38) resulting in decreased production of neuroexcitatory/proinflammatory cytokines (TNF-α, IL-1β) and increased formation of the neuroprotective/anti-inflammatory IL-10. The second involves inhibition of redox-mediated posttranslational tyrosine nitration and modification (inactivation) of glia-restricted proteins known to play key roles in regulating synaptic glutamate homeostasis: the glutamate transporter GLT-1 and glutamine synthetase. Our results unravel a mechanistic link into biomolecular signaling pathways employed by A3AR activation in neuropathic pain while providing the foundation to consider use of A3AR Agonists as therapeutic agents in patients with chemotherapy-induced peripheral neuropathy.
