Vol. 295, Issue 3, 1165-1174, December 2000

ABT-702 (4-Amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin- 3-yl)pyrido[2,3-d]pyrimidine), a Novel Orally Effective Adenosine Kinase Inhibitor with Analgesic and Anti-Inflammatory Properties. II. In Vivo Characterization in the Rat

Elizabeth A. Kowaluk, Joe Mikusa , Carol T. Wismer, Chang Z. Zhu, Edmund Schweitzer, James J. Lynch, Chih-Hung Lee, Meiqun Jiang, Shripad S. Bhagwat¹ , Arthur Gomtsyan, Jeff McKie, Bryan F. Cox, James Polakowski, Glenn Reinhart, Michael Williams and Michael F. Jarvis

Neurological and Urological Diseases Research (E.A.K., J.M., C.T.W., C.Z.Z., E.S., J.J.L., C.-H.L., M.J., S.S.B., A.G., J.M., M.W., M.F.J.) and Integrative Pharmacology Pharmaceutical Products Division (B.F.C., J.P., G.R.), Abbott Laboratories, Abbott Park, Illinois

Adenosine kinase (AK; EC 2.7.1.20) is a key intracellular enzyme regulating intra-and extracellular concentrations of adenosine (ADO), an endogenous neuromodulator, antinociceptive, and anti-inflammatory autocoid. AK inhibition provides a means of potentiating local tissue concentrations of endogenous ADO, and AK inhibitors may have therapeutic potential as analgesic and anti-inflammatory agents. The effects of ABT-702, a novel, potent (IC₅₀ = 1.7 nM), and selective non-nucleoside AK inhibitor were examined in rat models of nociception and acute inflammation. ABT-702 was orally effective and fully efficacious to suppress nociception in a spectrum of pain models in the rat, including carrageenan-induced thermal hyperalgesia, the formalin test of persistent pain, and models of nerve injury-induced and diabetic neuropathic pain (tactile allodynia after L5/L6 spinal nerve ligation or streptozotocin injection, respectively.) ABT-702 was especially potent at relieving inflammatory thermal hyperalgesia (ED₅₀ = 5 µmol/kg p.o.). ABT-702 was also effective in the carrageenan-induced paw edema model of acute inflammation (ED₅₀ = 70 µmol/kg p.o.). The antinociceptive and anti-inflammatory effects of ABT-702 were blocked by selective ADO receptor antagonists, consistent with endogenous ADO accumulation and ADO receptor activation as a mechanism of action. The antinociceptive effects of ABT-702 were not blocked by the opioid antagonist naloxone. In addition, ABT-702 showed less potential to develop tolerance to its antinociceptive effects compared with morphine. ABT-702 had no significant effect on rotorod performance or heart rate (at 30-300 µmol/kg p.o.), mean arterial pressure (at 30-100 µmol/kg p.o.), or exploratory locomotor activity (at 10 µmol/kg p.o.). Thus, ABT-702 is a novel, non-nucleoside AK inhibitor, with a nonopioid, non-nonsteroidal anti-inflammatory drug mechanism of action, which shows antinociceptive and anti-inflammatory activity in vivo.