Design, synthesis, and structure-activity relationship of 6-alkynylpyrimidines as potent adenosine kinase inhibitors.
Adenosine (ADO) is an extracellular signaling molecule within the central and peripheral nervous system. Its concentration is increased at sites of tissue injury and inflammation. One of the mechanisms by which antinociceptive and antiinflammatory effects of ADO can be enhanced consists of inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO. Novel nonnucleoside AK inhibitors based on 4-amino-6-alkynylpyrimidines were prepared, and the importance of the length of the linker at the 5-position for high affinity AK inhibition was demonstrated. Compounds with 2- and 3-atom linkers were the most potent AK inhibitors. Optimization of their physicochemical properties led to 31a and 37a that effectively reduced pain and inflammation in animal models.
Gomtsyan
Arthur
A
Neuroscience Research, Global Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. authur.r.gomtsyan@abbott.com
Didomenico
Stanley
S
Lee
Chih-Hung
CH
Matulenko
Mark A
MA
Kim
Ki
K
Kowaluk
Elizabeth A
EA
Wismer
Carol T
CT
Mikusa
Joe
J
Yu
Haixia
H
Kohlhaas
Kathy
K
Jarvis
Michael F
MF
Bhagwat
Shripad S
SS
D000241:Adenosine / Q000378:metabolism; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010147:Pain Measurement; D010766:Phosphorylation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C464666:4-amino-5-((2-chlorobenzyl)methylamino)-6-(6-(4-morpholinyl)-3-pyridinylethynyl)pyrimidine; C464667:4-amino-5-(benzylmethylaminomethyl)-6-(6-(4-morpholinyl)-3-pyridinylethynyl)pyrimidine; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D009025:Morpholines; D011725:Pyridines; D011743:Pyrimidines; D000248:Adenosine Kinase; D000241:Adenosine