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

Histamine H-3 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 H-3 receptor antagonists. ABT-239 binds to recombinant human and rat H-3 receptors with high affinity, with pK(i) values of 9.4 and 8.9, respectively, and is over 1000-fold selective versus human H-1, H-2, and H-4 histamine receptors. ABT-239 is a potent H-3 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-[S-35]thio) triphosphate ([S-35]GTP gamma S) 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 [H-3]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 (pA(2) = 8.7). Additionally, ABT-239 is a potent inverse agonist, inhibiting constitutive [S-35]GTP gamma S binding at both rat and human H-3 receptors with respective pEC(50) 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 H-3 receptor antagonist/inverse agonist with similar high potency in both human and rat and favorable drug-like properties.