title: 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.
abstract: 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]GTPgammaS) 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]GTPgammaS 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 t1/2 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.
authors.affiliation: Neuroscience Research, Abbott Laboratories, R4MN, AP9A, 100 Abbott Park Road, Abbott Park, IL 60064, USA. tim.esbenshade@abbott.com
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Esbenshade
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Fox
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Krueger
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Miller
authors.forename: Chae Hee
authors.initials: CH
authors.lastname: Kang
authors.forename: Lynne I
authors.initials: LI
authors.lastname: Denny
authors.forename: David G
authors.initials: DG
authors.lastname: Witte
authors.forename: Betty B
authors.initials: BB
authors.lastname: Yao
authors.forename: Liping
authors.initials: L
authors.lastname: Pan
authors.forename: Jill
authors.initials: J
authors.lastname: Wetter
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: Youssef L
authors.initials: YL
authors.lastname: Bennani
authors.forename: Marlon D
authors.initials: MD
authors.lastname: Cowart
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Hancock
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001572:Benzofurans / Q000493:pharmacokinetics / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003001:Cloning, Molecular; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000187:drug effects*
chemical_list: D001572:Benzofurans; D006633:Histamine Antagonists; D018377:Neurotransmitter Agents; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C496397:benzonitrile, 4-(2-(2-((2r)-2-methyl-1-pyrrolidinyl)ethyl)-5-benzofuranyl)-; D000262:Adenylyl Cyclases; D002118:Calcium