Identification of 4-amino-2-cyclohexylaminoquinazolines as metabolically stable melanin-concentrating hormone receptor 1 antagonists |
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Authors: | Kanuma Kosuke Omodera Katsunori Nishiguchi Mariko Funakoshi Takeo Chaki Shigeyuki Nagase Yasuko Iida Izumi Yamaguchi Jun-Ichi Semple Graeme Tran Thuy-Anh Sekiguchi Yoshinori |
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Affiliation: | Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan. |
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Abstract: | The optimization of the distance between two key pharmacophore features within our first hit compounds 1a and 2a led to the identification of a new class of potent non-peptidic antagonists for the MCH-R1, based around 4-amino-2-cyclohexylaminoquinazolines. In particular, ATC0065 (2c), N2-[cis-4-([2-[4-Bromo-2-(trifluoromethoxy)phenyl]ethyl]amino)cyclohexyl]-N4,N4-dimethylquinazoline-2,4-diamine dihydrochloride, bound with high affinity to the MCH-R1 (IC50 value of 16 nM) and showed good metabolic stability in liver microsomes from human and rat. |
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