Adenosine kinase inhibitors. 5. Synthesis, enzyme inhibition, and analgesic activity of diaryl-erythro-furanosyltubercidin analogues.
Adenosine is an endogenous neuromodulator that when produced in the central and the peripheral nervous systems has anticonvulsant, anti-inflammatory, and analgesic properties. However, efforts to use adenosine receptor agonists are plagued by dose-limiting cardiovascular side effects. As an alternative, we explored the use of adenosine kinase inhibitors (AKIs) as potential antiseizure agents and demonstrated an adenosine receptor mediated therapeutic effect in the absence of overt cardiovascular side effects. These activities were associated with elevation of extracellular adenosine concentrations due to inhibition of AK in a site and event specific manner. Several tubercidin based AKIs, including the ribo- and lyxo-furanosyltubercidin analogues as well as the newly discovered erythro-furanosyltubercidin analogues, designed to prevent 5'-O-phosphorylation and associated toxicities, were tested for their analgesic activity in the rat formalin paw model. Described herein are the synthesis, enzyme inhibition structure-activity relationships (SARs) of erythro-furanosyltubercidin analogues, and SARs of analgesic activity of various classes of AKIs. Also reported is the characterization of a lead AKI, 19d (GP3966), an orally bioavailable compound (F% = 60% in dog) which exhibits broad-spectrum analgesic activities (ED50 < or = 4 mg/kg, per os) that are reversible with an adenosine receptor antagonist (theophylline).
Boyer
Serge H
SH
Metabasis Therapeutics Inc., 9390 Towne Centre Drive, San Diego, California 92121, USA. boyer@mbasis.com
Ugarkar
Bheemarao G
BG
Solbach
Joel
J
Kopcho
Joseph
J
Matelich
Michael C
MC
Ollis
Kristin
K
Gomez-Galeno
Jorge E
JE
Mendonca
Rohan
R
Tsuchiya
Megumi
M
Nagahisa
Atsushi
A
Nakane
Masami
M
Wiesner
James B
JB
Erion
Mark D
MD
D000241:Adenosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000700:Analgesics / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002144:Callithrix; D004285:Dogs; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014372:Tubercidin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
C505565:4-N-(4-fluorophenyl)amino-5-phenyl-7-furanosylpyrrolo(2,3-d)pyrimidine; D000700:Analgesics; D000248:Adenosine Kinase; D000241:Adenosine; D014372:Tubercidin