title: Heterocyclic replacement of the central phenyl core of diamine-based histamine H3 receptor antagonists.
abstract: A series of small molecules consisting of a heterocyclic core flanked by two basic functionalities were synthesized and screened for in vitro affinity at the human histamine H(3) receptor (hH(3)R). Nine of the twenty-eight compounds tested were found to possess a hH(3)R K(i) of less than 5 nM and consisted of a diverse range of central hetero-aromatic linkers (pyridine, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, and pyrrole). One member of this series, (4-isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone (37), was found to be a high affinity, selective antagonist that crosses the blood-brain barrier and occupies H(3) receptors after oral administration in the rat.
authors: Johnson & Johnson Pharmaceutical Research and Development, LLC, San Diego, CA 92121, United States. dswanso1@its.jnj.com
authors: Devin M
authors: DM
authors: Swanson
authors: Chandra R
authors: CR
authors: Shah
authors: Brian
authors: B
authors: Lord
authors: Kirsten
authors: K
authors: Morton
authors: Lisa K
authors: LK
authors: Dvorak
authors: Curt
authors: C
authors: Mazur
authors: Richard
authors: R
authors: Apodaca
authors: Wei
authors: W
authors: Xiao
authors: Jamin D
authors: JD
authors: Boggs
authors: Mark
authors: M
authors: Feinstein
authors: Sandy J
authors: SJ
authors: Wilson
authors: Ann J
authors: AJ
authors: Barbier
authors: Pascal
authors: P
authors: Bonaventure
authors: Timothy W
authors: TW
authors: Lovenberg
authors: Nicholas I
authors: NI
authors: Carruthers
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002460:Cell Line; D003959:Diamines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D054828:Histamine H3 Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*
chemical_list: D003959:Diamines; D054828:Histamine H3 Antagonists; D018100:Receptors, Histamine H3