2-Cyclohexylcarbonylbenzimidazoles as potent, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonists
| Autor: | Yasuyuki Ishii, Hiroshi Miyazoe, Akio Ohno, Takeshi Tanaka, Takanobu Mochidome, Hirobumi Takahashi, Mioko Hirayama, Hiroshi Kawamoto, Kiyoshi Tadano, Masanori Asai, Izumi Yamamoto, Takashi Yoshizumi, Tetsuya Kato, Kensuke Kobayashi, Takahiro Fukuroda, Takeshi Tani, Osamu Okamoto, Minaho Uchiyama, Hiroshi Nakashima, Satoshi Ozaki, Satoru Ito, Hisashi Ohta, Atsushi Shimizu |
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| Rok vydání: | 2009 |
| Předmět: |
Stereochemistry
Narcotic Antagonists Clinical Biochemistry Administration Oral Pharmaceutical Science Biochemistry Chemical synthesis Nociceptin Receptor Cell Line Dogs Cyclohexanes In vivo Drug Discovery medicine Animals Humans ATP Binding Cassette Transporter Subfamily B Member 1 Receptor Molecular Biology P-glycoprotein biology Chemistry Organic Chemistry Antagonist Brain Haplorhini In vitro Rats Nociceptin receptor Opioid Hyperalgesia Receptors Opioid biology.protein Molecular Medicine Benzimidazoles medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 19:3096-3099 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2009.04.023 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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