title: Synthesis, structure-activity relationships, and biological profiles of a dihydrobenzoxathiin class of histamine H(3) receptor inverse agonists.
abstract: A series of novel dihydrobenzoxathiin derivatives was synthesized and evaluated as potent human histamine H(3) receptor inverse agonists. After systematic modification of lead 1a, the potent and selective histamine H(3) inverse agonist 1-(3-{4-[(2S,3S)-8-methoxy-3-methyl-4,4-dioxido-2,3-dihydro-1,4-benzoxathiin-2-yl]phenoxy}propyl)pyrrolidine (5k) was identified. Compound 5k showed good pharmacokinetic profiles and brain penetrability in laboratory animals. After 3mg/kg oral administration of 5k, significant elevation of brain histamine levels was observed in rats where the brain H(3) receptor was fully occupied.
authors.affiliation: Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Sasaki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nagase
authors.forename: Takashi
authors.initials: T
authors.lastname: Mizutani
authors.forename: Sayaka
authors.initials: S
authors.lastname: Ito
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mitobe
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Maki
authors.initials: M
authors.lastname: Kanesaka
authors.forename: Ryo
authors.initials: R
authors.lastname: Yoshimoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Norihiro
authors.initials: N
authors.lastname: Takenaga
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tokita
authors.forename: Nagaaki
authors.initials: N
authors.lastname: Sato
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D010075:Oxathiins / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D010075:Oxathiins; D018100:Receptors, Histamine H3; C500019:dihydrobenzoxathiin