Inhaled adenosine A(2A) receptor agonists for the treatment of chronic obstructive pulmonary disease.
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.
Mantell
Simon J
SJ
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Kent CT13 9NJ, United Kingdom.
Stephenson
Peter T
PT
Monaghan
Sandra M
SM
Maw
Graham N
GN
Trevethick
Michael A
MA
Yeadon
Michael
M
Keir
Ruth F
RF
Walker
Don K
DK
Jones
Rhys M
RM
Selby
Matthew D
MD
Batchelor
David V
DV
Rozze
Stuart
S
Chavaroche
Helene
H
Hobson
Tim J
TJ
Dodd
Peter G
PG
Lemaitre
Arnaud
A
Wright
Karen N
KN
Stuart
Emilio F
EF
D000241:Adenosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists; D000280:Administration, Inhalation; D000284:Administration, Oral; D000588:Amines / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D006168:Guinea Pigs; D006801:Humans; D008168:Lung / Q000378:metabolism; D010627:Phenethylamines / Q000493:pharmacokinetics / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
D058908:Adenosine A2 Receptor Agonists; D000588:Amines; D010627:Phenethylamines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine