2-Cyclohexylcarbonylbenzimidazoles as potent, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonists.
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.
Kobayashi
Kensuke
K
Tsukuba Research Institute, Banyu Pharmaceutical Co, Ltd, Tsukuba, Ibaraki, Japan.
Uchiyama
Minaho
M
Takahashi
Hirobumi
H
Kawamoto
Hiroshi
H
Ito
Satoru
S
Yoshizumi
Takashi
T
Nakashima
Hiroshi
H
Kato
Tetsuya
T
Shimizu
Atsushi
A
Yamamoto
Izumi
I
Asai
Masanori
M
Miyazoe
Hiroshi
H
Ohno
Akio
A
Hirayama
Mioko
M
Ozaki
Satoshi
S
Tani
Takeshi
T
Ishii
Yasuyuki
Y
Tanaka
Takeshi
T
Mochidome
Takanobu
T
Tadano
Kiyoshi
K
Fukuroda
Takahiro
T
Ohta
Hisashi
H
Okamoto
Osamu
O
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001562:Benzimidazoles; D003510:Cyclohexanes; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor