Document Detail


Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists.
MedLine Citation:
PMID:  21917455     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
During our efforts to identify a series of potent, selective, orally active human Orexin-2 Receptor (OX2R) antagonists, we elucidated structure-activity relationship (SAR) on the 7-position of a benzoxazepine scaffold by utilizing Hammett σ(p) and Hansch-Fujita π value as aromatic substituent constants. The attempts led to the discovery of compound 1m, possessing good in vitro potency with over 100-fold selectivity against OX1R, good metabolic stability in human and rat liver microsome, good oral bioavailability in rats, and in vivo antagonistic activity in rats by oral administration.
Authors:
Tatsuhiko Fujimoto; Jun Kunitomo; Yoshihide Tomata; Keiji Nishiyama; Masato Nakashima; Mariko Hirozane; Shin-Ichi Yoshikubo; Keisuke Hirai; Shogo Marui
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-8-30
Journal Detail:
Title:  Bioorganic & medicinal chemistry letters     Volume:  -     ISSN:  1464-3405     ISO Abbreviation:  -     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-9-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9107377     Medline TA:  Bioorg Med Chem Lett     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011 Elsevier Ltd. All rights reserved.
Affiliation:
Medicinal Chemistry Research Laboratories, Takeda Pharmaceutical Company, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-1238, Japan.
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