Synthesis and structure-activity relationships of 5-heteroatom-substituted pyridopyrimidines as adenosine kinase inhibitors.
Under stressful conditions, many cells release adenosine to minimize tissue damage. Inhibition of intracellular adenosine kinase (AK) increases the local extracellular concentration of adenosine and its effect on traumatized tissue. The synthesis and SAR of a new series of pyridopyrimidines for the inhibition of AK are described. It was found that a range of analogs with position five substituted by an amine or ether functionality increased aqueous solubility while retaining the in vitro potency of initial leads. A narrower range of analogs was active in vivo in a rat inflammatory hyperalgesia model.
Gfesser
Gregory A
GA
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA. greg.gfesser@abbott.com
Bayburt
Erol K
EK
Cowart
Marlon
M
DiDomenico
Stanley
S
Gomtsyan
Arthur
A
Lee
Chih Hung
CH
Stewart
Andrew O
AO
Jarvis
Michael F
MF
Kowaluk
Elizabeth A
EA
Bhagwat
Shripad S
SS
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D011743:Pyrimidines; D000248:Adenosine Kinase