title: Design and evaluation of novel biphenyl sulfonamide derivatives with potent histamine H(3) receptor inverse agonist activity.
abstract: Antagonism of the histamine-H(3) receptor is one tactic being explored to increase wakefulness for the treatment of disorders such as excessive daytime sleepiness (EDS) as well as other sleep or cognitive disorders. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were shown to be potent and selective antagonists of the H(3) receptor. Several of these compounds demonstrated in vivo activity in a rat model of (R)-alpha-methyl histamine (RAMH) induced dipsogenia, and one compound (4e) provided an increase in wakefulness in rats as measured by polysomnographic methods. However, more detailed analysis of the PK/PD relationship suggested the presence of a common active metabolite which may preclude this series of compounds from further development.
authors.affiliation: Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121, USA. jcovel@arenapharm.com
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Covel
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Santora
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Smith
authors.forename: Rena
authors.initials: R
authors.lastname: Hayashi
authors.forename: Charlemagne
authors.initials: C
authors.lastname: Gallardo
authors.forename: Michael I
authors.initials: MI
authors.lastname: Weinhouse
authors.forename: Jason B
authors.initials: JB
authors.lastname: Ibarra
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Schultz
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Park
authors.forename: Scott A
authors.initials: SA
authors.lastname: Estrada
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hofilena
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Pulley
authors.forename: Brian M
authors.initials: BM
authors.lastname: Smith
authors.forename: Albert
authors.initials: A
authors.lastname: Ren
authors.forename: Marissa
authors.initials: M
authors.lastname: Suarez
authors.forename: John
authors.initials: J
authors.lastname: Frazer
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Edwards
authors.forename: Erin K
authors.initials: EK
authors.lastname: Hauser
authors.forename: Jodie
authors.initials: J
authors.lastname: Lorea
authors.forename: Graeme
authors.initials: G
authors.lastname: Semple
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Grottick
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry*; D015195:Drug Design; D054314:Drug Inverse Agonism; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013894:Thirst / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects
chemical_list: D001713:Biphenyl Compounds; D006633:Histamine Antagonists; D018100:Receptors, Histamine H3; D013449:Sulfonamides; C010574:biphenyl