Abstract
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists described. A sevenfold improvement in potency and 150-fold reduction in side-effect liability over the lead compound CGS-21680, were obtained.
MeSH terms
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Adenosine / analogs & derivatives*
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Adenosine / pharmacokinetics
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Adenosine / pharmacology
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Adenosine A2 Receptor Agonists*
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Administration, Inhalation
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Administration, Oral
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Amines / pharmacokinetics
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Amines / pharmacology
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Animals
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Guinea Pigs
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Humans
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Lung / metabolism
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Phenethylamines / pharmacokinetics
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Phenethylamines / pharmacology
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Pulmonary Disease, Chronic Obstructive / drug therapy*
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Pulmonary Disease, Chronic Obstructive / metabolism
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Rats
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Structure-Activity Relationship
Substances
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Adenosine A2 Receptor Agonists
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Amines
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Phenethylamines
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2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
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Adenosine