2-(4-(2-carboxyethyl)phenethylamino)-5--n-ethylcarboxamidoadenosine and Pulmonary-Disease--Chronic-Obstructive

Chronic obstructive pulmonary disease (COPD) is a neutrophilic inflammatory disorder that is weakly responsive to glucocorticoids. Identification of ways to enhance the anti-inflammatory activity of glucocorticoids is, therefore, a major research objective. Adenosine receptor agonists that target the A2B-receptor subtype are efficacious in several cell-based assays and preclinical models of inflammation. Accordingly, the present study was designed to determine if a selective A2B-receptor agonist, 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulphanyl]acetamide (Bay 60-6583), and a glucocorticoid, dexamethasone, in combination display putative anti-inflammatory activity that is superior to either drug alone. In BEAS-2B human airway epithelial cells stably transfected with cAMP-response element (CRE) and glucocorticoid response element (GRE) reporter constructs, Bay 60-6583 promoted CRE-dependent transcription and enhanced GRE-dependent transcription by an adenosine A2B-receptor-mediated mechanism that was associated with cAMP formation and abolished by an inhibitor of cAMP-dependent protein kinase. Analysis of the concentration-response relationship that described the enhancement of GRE-dependent transcription showed that Bay 60-6583 increased the magnitude of response without affecting the potency of dexamethasone. Bay 60-6583 and dexamethasone also induced a panel of genes that, collectively, could have benefit in COPD. These were categorized into genes that were induced in a positive cooperative manner (RGS2, p57(kip2)), an additive manner (TTP, BRL-1), or by Bay 60-6583 (CD200, CRISPLD2, SOCS3) or dexamethasone (GILZ) only. Thus, the gene induction "fingerprints" produced by Bay 60-6583 and dexamethasone, alone and in combination, were distinct. Collectively, through their actions on gene expression, an adenosine A2B-receptor agonist and a glucocorticoid administered together may have utility in the treatment of inflammatory disorders that respond suboptimally to glucocorticoids as a monotherapy.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Algorithms; Aminopyridines; Calcium; Cell Line; Cyclic AMP; Cyclic AMP Response Element Modulator; Cytosol; Dexamethasone; Epithelial Cells; Humans; Inflammation; Phenethylamines; Pulmonary Disease, Chronic Obstructive; Real-Time Polymerase Chain Reaction; Receptor, Adenosine A2B; Receptors, Glucocorticoid; Respiratory Mucosa; RNA, Messenger; Transfection

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. The pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists is described leading through to human pharmacokinetic data for a clinical candidate.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Administration, Inhalation; Adolescent; Adult; Animals; Chemistry, Pharmaceutical; Drug Design; Humans; Inhibitory Concentration 50; Lung; Male; Middle Aged; Models, Chemical; Phenethylamines; Pulmonary Disease, Chronic Obstructive; Purines; Rats; Structure-Activity Relationship; Triazoles

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.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Administration, Inhalation; Administration, Oral; Amines; Animals; Guinea Pigs; Humans; Lung; Phenethylamines; Pulmonary Disease, Chronic Obstructive; Rats; Structure-Activity Relationship