title: Novel substituted pyrrolidines are high affinity histamine H3 receptor antagonists.
abstract: Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H(3) receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H(3) receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Stocking
authors.forename: Leah
authors.initials: L
authors.lastname: Aluisio
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonaventure
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
authors.forename: Christine
authors.initials: C
authors.lastname: Dugovic
authors.forename: Anita
authors.initials: A
authors.lastname: Everson
authors.forename: Ian
authors.initials: I
authors.lastname: Fraser
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Jiang
authors.forename: Perry
authors.initials: P
authors.lastname: Leung
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.forename: Kiev S
authors.initials: KS
authors.lastname: Ly
authors.forename: Kirsten L
authors.initials: KL
authors.lastname: Morton
authors.forename: Diane
authors.initials: D
authors.lastname: Nepomuceno
authors.forename: Chandravadan R
authors.initials: CR
authors.lastname: Shah
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shelton
authors.forename: Akinola
authors.initials: A
authors.lastname: Soyode-Johnson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C550998:1-(2-(4-cyclobutyl-(1,4)diazepane-1-carbonyl)-4-(3-fluorophenoxy)pyrrolidin-1-yl)ethanone; D001381:Azepines; D054828:Histamine H3 Antagonists; D011759:Pyrrolidines; D018100:Receptors, Histamine H3