Inhaled adenosine A(2A) receptor agonists for the treatment of chronic obstructive pulmonary disease.
Mantell SJ, Stephenson PT, Monaghan SM, Maw GN, Trevethick MA, Yeadon M, Keir RF, Walker DK, Jones RM, Selby MD, Batchelor DV, Rozze S, Chavaroche H, Hobson TJ, Dodd PG, Lemaitre A, Wright KN, Stuart EF.
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.