Synthesis, structure-activity relationships, and biological profiles of a dihydrobenzoxathiin class of histamine H(3) receptor inverse agonists.
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.
Sasaki
Takahide
T
Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
Takahashi
Toshiyuki
T
Nagase
Tsuyoshi
T
Mizutani
Takashi
T
Ito
Sayaka
S
Mitobe
Yuko
Y
Miyamoto
Yasuhisa
Y
Kanesaka
Maki
M
Yoshimoto
Ryo
R
Tanaka
Takeshi
T
Takenaga
Norihiro
N
Tokita
Shigeru
S
Sato
Nagaaki
N
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
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D010075:Oxathiins; D018100:Receptors, Histamine H3; C500019:dihydrobenzoxathiin