title: 2-Cyclohexylcarbonylbenzimidazoles as potent, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonists.
abstract: The synthesis and biological evaluation of new potent opioid receptor-like 1 (ORL1) antagonists are presented. Conversion of the thioether linkage of the prototype [It is reported prior to this communication as a consecutive series.: Kobayashi, K.; Kato, T.; Yamamoto, I.; Shimizu, A.; Mizutani, S.; Asai, M.; Kawamoto, H.; Ito, S.; Yoshizumi, T.; Hirayama, M.; Ozaki, S.; Ohta, H.; Okamoto, O. Bioorg. Med. Chem. Lett., in press] to the carbonyl linker effectively reduces susceptibility to P-glycoprotein (P-gp) efflux. This finding led to the identification of 2-cyclohexylcarbonylbenzimizole analogue 7c, which exhibited potent ORL1 activity, excellent selectivity over other receptors and ion channels, and poor susceptibility to P-gp. Compound 7c also showed satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Furthermore, 7c showed good in vivo antagonism. Hence, 7c was selected as a clinical candidate for a brain-penetrable ORL1 antagonist.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Co, Ltd, Tsukuba, Ibaraki, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Minaho
authors.initials: M
authors.lastname: Uchiyama
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Ito
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshizumi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakashima
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kato
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shimizu
authors.forename: Izumi
authors.initials: I
authors.lastname: Yamamoto
authors.forename: Masanori
authors.initials: M
authors.lastname: Asai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyazoe
authors.forename: Akio
authors.initials: A
authors.lastname: Ohno
authors.forename: Mioko
authors.initials: M
authors.lastname: Hirayama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ozaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tani
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ishii
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Takanobu
authors.initials: T
authors.lastname: Mochidome
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Tadano
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fukuroda
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ohta
authors.forename: Osamu
authors.initials: O
authors.lastname: Okamoto
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D004285:Dogs; D000882:Haplorhini; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D009292:Narcotic Antagonists; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism; D000094942:Nociceptin Receptor
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001562:Benzimidazoles; D003510:Cyclohexanes; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor