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 = 76 nM, human Ki = 21 nM), and exhibited functional antagonism in blocking agonist-induced [35S]GTPγS binding (rat H3 Kb = 107 nM, human H3 Kb = 22 nM), 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 3 mg/kg were effective 60 min post dosing with an ED50 of 2.17 mg/kg and a blood EC50 of 639 ng/ml. In a model of osteoarthritis pain, oral doses of 0.1, 0.3, and 1 mg/kg were effective 1 h post dosing with an ED50 of 0.52 mg/kg and a blood EC50 of 233 ng/ml. The antinociceptive effect of A-960656 in both pain models was maintained after sub-chronic dosing up to 12 days. A-960656 had excellent rat pharmacokinetics (t1/2 = 1.9 h, 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.