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    
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.
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
Related Documents :
19923388 - Preventing food crises using a food policy approach.
25299618 - Chemical defense balanced by sequestration and de novo biosynthesis in a lepidopteran s...
23576778 - Asymmetry in pay-off predicts how familiar individuals respond to one another.
23850518 - The effectiveness of workplace dietary modification interventions: a systematic review.
18513758 - Analysis of change of red tide species in yodo river estuary by the numerical ecosystem...
22835228 - On the different growth conditions affecting silver antimicrobial efficacy on listeria ...
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:  -    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Point-of-sale alcohol promotions in the Perth and Sydney metropolitan areas.
Next Document:  Insight into eukaryotic topoisomerase II-inhibiting fused heterocyclic compounds in human cancer cel...