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Discovery of 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d]pyrimidine, an orally active, non-nucleoside adenosine kinase inhibitor..

Abstract
Adenosine (ADO) is an endogenous homeostatic inhibitory neuromodulator that reduces cellular excitability at sites of tissue injury and inflammation. Inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO, selectively increases ADO concentrations at sites of tissue trauma and enhances the analgesic and antiinflammatory actions of ADO. Optimization of the high-throughput screening lead, 4-amino-7-aryl-substituted pteridine (5) (AK IC(50) = 440 nM), led to the identification of compound 21 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d]pyrimidine, ABT-702), a novel, potent (AK IC(50) = 1.7 nM) non-nucleoside AK inhibitor with oral activity in animal models of pain and inflammation.
AuthorsC H Lee, M Jiang, M Cowart, G Gfesser, R Perner, K H Kim, Y G Gu, M Williams, M F Jarvis, E A Kowaluk, A O Stewart, S S Bhagwat
JournalJournal of medicinal chemistry (J Med Chem) Vol. 44 Issue 13 Pg. 2133-8 (Jun 21 2001) ISSN: 0022-2623 [Print] United States
PMID11405650 (Publication Type: Journal Article)
Chemical References
  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • Morpholines
  • Pyrimidines
  • Formaldehyde
  • ABT 702
  • Adenosine Kinase
Topics
  • Adenosine Kinase (antagonists & inhibitors)
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, pharmacology)
  • Drug Design
  • Enzyme Inhibitors (chemical synthesis, pharmacology)
  • Formaldehyde
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Morpholines (chemical synthesis, pharmacology)
  • Pain Measurement
  • Pyrimidines (chemical synthesis, pharmacology)
  • Rats
  • Tumor Cells, Cultured

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