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..
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.
Lee
C H
CH
Neurological and Urological Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6125, USA. lance.lee@abbott.com
Jiang
M
M
Cowart
M
M
Gfesser
G
G
Perner
R
R
Kim
K H
KH
Gu
Y G
YG
Williams
M
M
Jarvis
M F
MF
Kowaluk
E A
EA
Stewart
A O
AO
Bhagwat
S S
SS
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005557:Formaldehyde; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009025:Morpholines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010147:Pain Measurement; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D009025:Morpholines; D011743:Pyrimidines; D005557:Formaldehyde; C416933:ABT 702; D000248:Adenosine Kinase