Pharmacological characterization of A-960656, a histamine H₃ receptor antagonist with efficacy in animal models of osteoarthritis and neuropathic pain.

Histamine H3 receptor antagonists have been widely reported to improve performance in preclinical models of cognition, but more recently efficacy in pain models has also been described. Here, A-960656 ((R)-2-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-yl)pyridazin-3(2H)-one) was profiled as a new structural chemotype. A-960656 was potent in vitro in histamine H3 receptor binding assays (rat Ki=76nM, human Ki=21nM), and exhibited functional antagonism in blocking agonist-induced [35S]GTPγS binding (rat H3 Kb=107nM, human H3 Kb=22nM), and was highly specific for H3 receptors in broad screens for non-H3 sites. In a spinal nerve ligation model of neuropathic pain in rat, oral doses of 1 and 3mg/kg were effective 60min post dosing with an ED50 of 2.17mg/kg and a blood EC50 of 639ng/ml. In a model of osteoarthritis pain, oral doses of 0.1, 0.3, and 1mg/kg were effective 1h post dosing with an ED50 of 0.52mg/kg and a blood EC50 of 233ng/ml. The antinociceptive effect of A-960656 in both pain models was maintained after sub-chronic dosing up to 12days. A-960656 had excellent rat pharmacokinetics (t1/2=1.9h, 84% oral bioavailability) with rapid and efficient brain penetration, and was well tolerated in CNS behavioral safety screens. In summary, A-960656 has properties well suited to probe the pharmacology of histamine H3 receptors in pain. Its potency and efficacy in animal pain models provide support to the notion that histamine H3 receptor antagonists are effective in attenuating nociceptive processes.