title: Synthesis and structure-activity relationships of 5-heteroatom-substituted pyridopyrimidines as adenosine kinase inhibitors.
abstract: 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.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA. greg.gfesser@abbott.com
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Gfesser
authors.forename: Erol K
authors.initials: EK
authors.lastname: Bayburt
authors.forename: Marlon
authors.initials: M
authors.lastname: Cowart
authors.forename: Stanley
authors.initials: S
authors.lastname: DiDomenico
authors.forename: Arthur
authors.initials: A
authors.lastname: Gomtsyan
authors.forename: Chih Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Stewart
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Kowaluk
authors.forename: Shripad S
authors.initials: SS
authors.lastname: Bhagwat
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D011743:Pyrimidines; D000248:Adenosine Kinase