title: Structure-activity studies of 5-substituted pyridopyrimidines as adenosine kinase inhibitors.
abstract: The synthesis and SAR of a novel series of non-nucleoside pyridopyrimidine inhibitors of the enzyme adenosine kinase (AK) are described. It was found that pyridopyrimidines with a broad range of medium and large non-polar substituents at the 5-position potently inhibited AK activity. A narrower range of analogues was capable of potently inhibiting adenosine phosphorylation in intact cells indicating an enhanced ability of these analogues to penetrate cell membranes. Potent AK inhibitors were found to effectively reduce nociception in animal models of thermal hyperalgesia and persistent pain.
authors.affiliation: Neurological and Urological Diseases Research, Abbott Laboratories, Abhott Park, IL 60064, USA. marlon.d.cowart@abbott.com
authors.forename: M
authors.initials: M
authors.lastname: Cowart
authors.forename: C H
authors.initials: CH
authors.lastname: Lee
authors.forename: G A
authors.initials: GA
authors.lastname: Gfesser
authors.forename: E K
authors.initials: EK
authors.lastname: Bayburt
authors.forename: S S
authors.initials: SS
authors.lastname: Bhagwat
authors.forename: A O
authors.initials: AO
authors.lastname: Stewart
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: K L
authors.initials: KL
authors.lastname: Kohlhaas
authors.forename: S
authors.initials: S
authors.lastname: McGaraughty
authors.forename: C T
authors.initials: CT
authors.lastname: Wismer
authors.forename: J
authors.initials: J
authors.lastname: Mikusa
authors.forename: C
authors.initials: C
authors.lastname: Zhu
authors.forename: K M
authors.initials: KM
authors.lastname: Alexander
authors.forename: M F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: E A
authors.initials: EA
authors.lastname: Kowaluk
mesh_terms: D000248:Adenosine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D002463:Cell Membrane Permeability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006930:Hyperalgesia / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement / Q000187:drug effects; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D000248:Adenosine Kinase