Novel ORL1-selective antagonists with oral bioavailability and brain penetrability.
Following the discovery of 5-chloro-6-[piperazin-1-yl]-1H-benzimidazole as a novel pharmacophore for potent and selective ORL1 antagonist activity, optimization of this new lead by introduction of a methyl substitution on the piperazine ring resulted in a highly potent and selective, orally available, and brain penetrable ORL1 antagonist, 2-(tert-butylthio)-5-chloro-6-[(2R)-4-(2-hydroxyethyl)-2-methylpiperazin-1-yl]-1H-benzimidazole. Stereochemistry of the methyl substituent on the piperazine ring to control the functional activity of other opioid receptors is also described.
Okamoto
Osamu
O
Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Okubo-3, Tsukuba, Ibaraki 300-2611, Japan. osamu_okamoto@merck.com
Kobayashi
Kensuke
K
Kawamoto
Hiroshi
H
Ito
Satoru
S
Yoshizumi
Takashi
T
Yamamoto
Izumi
I
Hashimoto
Masaya
M
Shimizu
Atsushi
A
Takahashi
Hiroyuki
H
Ishii
Yasuyuki
Y
Ozaki
Satoshi
S
Ohta
Hisashi
H
D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D020650:Combinatorial Chemistry Techniques; D000882:Haplorhini; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009292:Narcotic Antagonists; D051381:Rats; D011957:Receptors, Opioid; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
C529701:2-(tert-butylthio)-5-chloro-6-((2R)-4-(2-hydroxyethyl)-2-methylpiperazin-1-yl)-1H-benzimidazole; D001562:Benzimidazoles; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor