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Overview

Balloon angioplasty involves the simultaneous activation of platelets and neutrophils. Activated platelets release mitogenic substances that cause smooth muscle cell proliferation and thereby contribute to restenosis. Activated neutrophils activate platelets and activated platelets activate neutrophils. Therefore the simultaneous activation of both cell types may be responsible for the exaggerated repair mechanisms resulting in restenosis of coronary blood vessels. Adenosine inhibits neutrophil activation, platelet activation and smooth muscle cell proliferation and stimulates endothelial cell proliferation predominantly through activation of A2A-receptors. Adenosine and A2A-selective agonists may be useful in the prevention of restenosis following balloon angioplasty.

01 Oct 1997·Drug Development Research

Pharmacology and toxicology of the A2A-adenosine receptor agonist 2- [(cyclohexylmethylene)hydrazino]adenosine (MRE-0470) in the rat

Author: Barrett, R. J. ; Sykes, A. ; Martin, Pauline L. ; Mossem, D. ; Wright, K. F. ; Droppleman, D. A.

2-[(Cyclohexylmethylene)hydrazino]adenosine (MRE-0470) is an A_2A-adenosine receptor agonist that is a potent and selective coronary vasodilator.As part of a preclin. program, the pharmacol. and toxicol. of MRE-0470 have been studied in the rat.In isolated vas deferens, MRE-0470 activated A_2B receptors (EC₅₀ = 6.3 nM) and at higher concentrations activated A_2B receptors (EC₅₀ = 13 μM).In atrial tissues, MRE-0470 produced neg. inotropic and chronotropic actions through activation of A₁ receptors (EC₅₀ ∼ 9 μM).MRE-0470 produced no pos. inotropic or chronotropic actions in atrial or ventricular tissues.In anesthetized, reflex-blocked rats, MRE-0470 produced a decrease in hindquarter perfusion pressure (A₂: ED₅₀ = 0.31 μg) and a decrease in heart rate (A₁: ED₅₀ = 620 μg).In conscious rats, MRE-0470 (0.04-117 μ/kg bolus or 0.03-150 μ/kg/min infusion) produced dose-dependent hypotension and reflex tachycardia.MRE-0470 was rapidly eliminated from rat plasma with an elimination half-life of 10 min.In toxicol. studies, once per day 10-min i.v. infusions of 3, 30, or 150 μg/kg/min MRE-0470 for 14 consecutive days resulted in no deaths and no changes in blood chem., but resulted in decreased motor activity and dose-related cardiomyopathy.Cardiomyopathy did not occur following single doses of MRE-0470.The incidence of this lesion is related to the duration of the repeated reflex tachycardia.These studies show that MRE-0470 is a potent and selective A_2A receptor agonist in the rat.The observed toxicol. of MRE-0470 is consistent with the exaggerated pharmacol. due to high-dose drug administration.

01 Apr 1997·Drug Development Research

Pharmacology of 2-cyclohexylmethylidenehydrazinoadenosine (WRC-0470), a novel, short-acting adenosine A2A receptor agonist that produces selective coronary vasodilation

Author: Martin, Pauline L. ; Linden, Joel ; Barrett, Richard J. ; Abraham, William M.

I.v. adenosine (ADO) is used clin. to produce coronary vasodilation during myocardial perfusion imaging studies.The coronary vasodilation produced by ADO is due to activation of A_2A-receptors.An analog of ADO WRC-0470 was developed that was selective for the A_2A-receptor.The present studies were designed to determine whether WRC-0470 could produce selective coronary vasodilation but be devoid of the side effects that ADO possesses due to activation of A₁, A_2B, or A₃ adenosine receptors.In guinea pig isolated tissues, WRC-0470 was a potent coronary vasodilator (A_2A: A₅₀ = 1.5 nM) but was a weak neg. inotropic or chronotropic agent (A₁: A₅₀ = 40-140 μM) and was a weak vasodilator in the aorta (A_2B: A₅₀ = 49 μM).WRC-0470 bound to human A₁, A_2A, A_2B, and A₃ receptors with affinities of 48 μM, 270 nM, 430 μM, and 903 nM, resp.I.v. infusion of WRC-0470 (0.1-0.6 μg/kg/min ×10 min) to anesthetized and conscious dogs produced coronary vasodilation at doses that produced little or no systemic hypotension.Only at infusion doses in excess of 0.6 μg/kg/min was a significant decrease in blood pressure and a decrease in left ventricular pressure observedWRC-0470 had no consistent or significant effect on heart rate, PR interval, QRS interval, or QT interval.WRC-0470 was rapidly cleared from dog plasma with an elimination half-life of 6 min.In an allergic sheep model of asthma, the clin. predicted dose of WRC-0470 (≤0.6 μg/kg/min) produced no significant increase in lung resistance whereas the clin. dose of ADO (140 μg/kg/min) produced a 100% increase in lung resistance.WRC-0470 is a short-acting A_2A selective ADO agonist that produces selective coronary vasodilation in the dog.Because WRC-0470 is a weak agonist at A₁, A_2B, and A₃ receptors, it is predicted that WRC-0470 will produce fewer side effects clin. than does ADO.

100 Deals associated with ADERIS Pharmaceuticals, Inc.

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100 Translational Medicine associated with ADERIS Pharmaceuticals, Inc.

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Pipeline

Pipeline Snapshot as of 02 Feb 2025

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

WRC-0342 ( A1R )	Cardiovascular Diseases More	Discontinued
WRC-0542 ( A1R )	Cardiovascular Diseases More	Discontinued
DTI-0026 ( LT )	Glomerulonephritis More	Discontinued
N-0861 ( A1R )	Myocardial Infarction More	Discontinued
DTI-0017 ( A1R )	Heart Failure More	Discontinued