New tetrahydrobenzindoles as potent and selective 5-HT(7) antagonists with increased In vitro metabolic stability.
Chemical modifications of compound 1 (DR4004), a potent, selective antagonist of the 5-HT(7) receptor, were conducted with the aim of improving its metabolic stability. Halogenation of putative sites of oxidative metabolism afforded compounds 7-10, which retained high affinity and selectivity for the 5-HT(7) receptor, and showed increased in vitro metabolic stability. Compound 10 (DR4485) showed oral bioavailability, and should be a useful tool for evaluating the therapeutic potential of 5-HT(7) antagonists.
Kikuchi
Chika
C
Pharmaceutical Research Center, Meiji Seika Kaisha Ltd., 760Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. chika_kikuchi@meiji.co.jp
Suzuki
Hisashi
H
Hiranuma
Toyokazu
T
Koyama
Masao
M
D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004355:Drug Stability; D006219:Halogens; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000187:drug effects; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
C472242:DR-4004; D006219:Halogens; D007211:Indoles; D011725:Pyridines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor; D000242:Cyclic AMP