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

• Published in: Journal of medicinal chemistry Vol. 44; no. 13; pp. 2133 - 2138
• Main Authors: Lee, Chih-Hung, Jiang, Meiqun, Cowart, Marlon, Gfesser, Greg, Perner, Richard, Kim, Ki Hwan, Gu, Yu Gui, Williams, Michael, Jarvis, Michael F, Kowaluk, Elizabeth A, Stewart, Andrew O, Bhagwat, Shripad S
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.06.2001; Amer Chemical Soc
• Subjects: Adenosine Kinase - antagonists & inhibitors; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Chemistry, Medicinal; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Formaldehyde; Humans; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Conformation; Morpholines - chemical synthesis; Morpholines - pharmacology; Neuropharmacology; Pain Measurement; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Rats; Science & Technology; Tumor Cells, Cultured; ABT-702 4-AMINO-5-(3-BROMOPHENYL)-7-(6-MORPHOLINO-PYRIDIN-3-YL)PYRIDO<2,3-D>PYRI; ANTIINFLAMMATORY PROPERTIES; RAT; RECEPTORS; Enzyme; Nitrogen heterocycle; Transferases; Non nucleoside compound; Antiinflammatory agent; Oral administration; Combinatorial chemistry; Enzyme inhibitor; Morpholine derivatives; In vitro; Pyridine derivatives; Dose activity relation; Screening; In vivo; Analgesic; Structure activity relation; Adenosine kinase; Animal; Chemical compound library; Bicyclic compound; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000314x

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 IC50 = 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 IC50 = 1.7 nM) non-nucleoside AK inhibitor with oral activity in animal models of pain and inflammation.