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NEUROPHARMACOLOGY

Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: I. Potent and Selective Histamine H₃ Receptor Antagonist with Drug-Like Properties

Neuroscience Research, Global Pharmaceutical Research Division, Abbott Laboratories, Abbott Park, Illinois (T.A.E., G.B.F., K.M.K., T.R.M., C.H.K., D.G.W., B.B.Y., L.P., J.W., K.M., M.D.C., J.P.S., A.A.H.); Pfizer, Ann Arbor, Michigan (L.I.D.); and Vertex Pharmaceuticals, Cambridge, Massachusetts (Y.L.B.)

Histamine H₃ receptor antagonists are being developed to treat a variety of neurological and cognitive disorders that may be ameliorated by enhancement of central neurotransmitter release. Here, we present the in vitro pharmacological and in vivo pharmacokinetic profiles for the nonimidazole, benzofuran ligand ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] and compare it with several previously described imidazole and nonimidazole H₃ receptor antagonists. ABT-239 binds to recombinant human and rat H₃ receptors with high affinity, with pK_i values of 9.4 and 8.9, respectively, and is over 1000-fold selective versus human H₁, H₂, and H₄ histamine receptors. ABT-239 is a potent H₃ receptor antagonist at recombinant human and rat receptors, reversing agonist-induced changes in cAMP formation (pK_b = 7.9 and 7.6, respectively), guanosine 5'-O-(3-[³⁵S]thio) triphosphate ([³⁵S]GTPS) binding (pK_b = 9.0 and 8.3, respectively), and calcium mobilization (human pK_b = 7.9). ABT-239 also competitively reversed histamine-mediated inhibition of [³H]histamine release from rat brain cortical synaptosomes (pK_b = 7.7) and agonist-induced inhibition of contractile responses in electric field stimulated guinea pig ileal segments (pA₂ = 8.7). Additionally, ABT-239 is a potent inverse agonist, inhibiting constitutive [³⁵S]GTPS binding at both rat and human H₃ receptors with respective pEC₅₀ values of 8.9 and 8.2. ABT-239 demonstrates good pharmacokinetic characteristics in rat, dog, and monkey with t_1/2 values ranging from 4 to 29 h, corresponding with clearance values and metabolic turnover in liver microsomes from these species, and good oral bioavailability ranging from 52 to 89%. Thus, ABT-239 is a selective, nonimidazole H₃ receptor antagonist/inverse agonist with similar high potency in both human and rat and favorable drug-like properties.

Address correspondence to: Dr. Timothy A. Esbenshade, Neuroscience Research, Abbott Laboratories, R4MN, AP9A, 100 Abbott Park Road, Abbott Park, IL 60064. E-mail: tim.esbenshade{at}abbott.com

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