- 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
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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, experiments with ligand-based drug designs based on 1 and a docking study were 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.
- Kasai, Shizuo,Kamata, Makoto,Masada, Shinichi,Kunitomo, Jun,Kamaura, Masahiro,Okawa, Tomohiro,Takami, Kazuaki,Ogino, Hitomi,Nakano, Yoshihide,Ashina, Shuntarou,Watanabe, Kaoru,Kaisho, Tomoko,Imai, Yumi N.,Ryu, Sunghi,Nakayama, Masaharu,Nagisa, Yasutaka,Takekawa, Shiro,Kato, Koki,Murata, Toshiki,Suzuki, Nobuhiro,Ishihara, Yuji
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p. 4336 - 4351
(2012/07/01)
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- Synthesis and antiaggregator activity of some new derivatives of 4H-benzopyran-4-one
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A series of 2--4H-1-benzopyran-4-one analogues 7a-7e was synthesized by the reaction with 3',4'-diaminoflavone and aliphatic carboxylic acids. 3',4'-Diaminoflavone 6 was prepared via the reduction of 2-(4-amino-3-nitrophenyl)-4H-1-benzopyran-4-one 5a.The compounds 7a-e and 14a-f were tested in vitro for their inhibitory activities against human platelet aggregation induced by collagen, ADP and A23187.The compound with a COOR group as a side chain, 2-(2-akyloxycarbonyl-2,3-dihydro-1,4-benzodioxin -6-yl)-4H-1-benzopyran-4-one 14a-f, haspotent activity, and so compound 13 was also prepared as an analogue of series 14 and tested for its antiaggregator activity. 4H-1-benzopyran-4-one/ benzodioxane/ benzimidazole/ human platelet/ aggregation
- Goeker, H.,Ayhan, G.,Tuncbilek, M.,Ertan, R.,Leoncini, G.,et al.
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p. 561 - 568
(2007/10/02)
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