Document Detail


Synthesis, Structure-Activity Relationship, and Pharmacological Studies of Novel Melanin-Concentrating Hormone Receptor 1 Antagonists 3-Aminomethylquinolines: Reducing human Ether-a-go-go-Related Gene (hERG)-Associated Liabilities.
MedLine Citation:
PMID:  22490048     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor-1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K+ channel inhibition in a patch-clamp study. To decrease hERG K+ channel inhibition, ligand-based drug designs based on 1 and a docking study was conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)ethyl]amino group as the amine portion eliminated hERG K+ channel inhibitory activity in a patch-clamp study, leading to the discovery of N-{3-[(1R)-1-{[2-(acetylamino)ethyl]amino}ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R)-10h was performed to determine the molecule's absolute configuration.
Authors:
Shizuo Kasai; Makoto Kamata; Shinichi Masada; Jun Kunitomo; Masahiro Kamaura; Tomohiro Okawa; Kazuaki Takami; Hitomi Ogino; Yoshihide Nakano; Shuntarou Ashina; Kaoru Watanabe; Tomoko Kaisho; Masaharu Nakayama; Yumi N Imai; Sunghi Ryu; Yasutaka Nagisa; Shiro Takekawa; Koki Kato; Toshiki Murata; Nobuhiro Suzuki; Yuji Ishihara
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-10
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-4-11     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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