title: Identification of biaryl sulfone derivatives as antagonists of the histamine H₃ receptor: discovery of (R)-1-(2-(4'-(3-methoxypropylsulfonyl)biphenyl-4-yl)ethyl)-2-methylpyrrolidine (APD916).
abstract: The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.
authors.affiliation: Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. gsemple@arenapharm.com
authors.forename: Graeme
authors.initials: G
authors.lastname: Semple
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Santora
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Smith
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Covel
authors.forename: Rena
authors.initials: R
authors.lastname: Hayashi
authors.forename: Charlemagne
authors.initials: C
authors.lastname: Gallardo
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: 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 E
authors.initials: JE
authors.lastname: Edwards
authors.forename: Ryan
authors.initials: R
authors.lastname: Hart
authors.forename: Erin K
authors.initials: EK
authors.lastname: Hauser
authors.forename: Jodie
authors.initials: J
authors.lastname: Lorea
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Grottick
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry; D006633:Histamine Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D011759:Pyrrolidines / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry*; D012890:Sleep / Q000187:drug effects; D013450:Sulfones / Q000737:chemistry*; D013696:Temperature; D014851:Wakefulness / Q000187:drug effects
chemical_list: C573772:(R)-1-(2-(4'-(3-methoxypropylsulfonyl)biphenyl-4-yl)ethyl)-2-methylpyrrolidine; D001713:Biphenyl Compounds; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006633:Histamine Antagonists; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; D013450:Sulfones; C032519:pyrrolidine