کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10587852 | 981440 | 2011 | 14 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Discovery, synthesis, and structure-activity relationship of 6-aminomethyl-7,8-dihydronaphthalenes as human melanin-concentrating hormone receptor 1 antagonists
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کلمات کلیدی
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: Discovery, synthesis, and structure-activity relationship of 6-aminomethyl-7,8-dihydronaphthalenes as human melanin-concentrating hormone receptor 1 antagonists Discovery, synthesis, and structure-activity relationship of 6-aminomethyl-7,8-dihydronaphthalenes as human melanin-concentrating hormone receptor 1 antagonists](/preview/png/10587852.png)
چکیده انگلیسی
Human melanin-concentrating hormone receptor 1 (hMCHR1) antagonists are promising targets for obesity treatment. We identified the tetrahydronaphthalene derivative 1a with modest binding affinity for hMCHR1 by screening an in-house G protein-coupled receptor (GPCR) ligand library. We synthesized a series of 6-aminomethyl-5,6,7,8-tetrahydronaphthalenes and evaluated their activity as hMCHR1 antagonists. Modification of the biphenylcarbonylamino group revealed that the biphenyl moiety played a crucial role in the interaction of the antagonist with the receptor. The stereoselective effect of the chiral center on binding affinity generated the novel 6-aminomethyl-7,8-dihydronaphthalene scaffold without a chiral center. Optimization of the amino group led to the identification of a potent antagonist 2s (4â²-fluoro-N-[6-(1-pyrrolidinylmethyl)-7,8-dihydro-2-naphthalenyl][1,1â²-biphenyl]-4-carboxamide), which significantly inhibited the nocturnal food intake in rats after oral administration. Pharmacokinetic analysis confirmed that 2s had good oral bioavailability and brain penetrance. This antagonist appears to be a viable lead compound that can be used to develop a promising therapy for obesity.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 19, Issue 18, 15 September 2011, Pages 5539-5552
Journal: Bioorganic & Medicinal Chemistry - Volume 19, Issue 18, 15 September 2011, Pages 5539-5552
نویسندگان
Makoto Kamata, Toshiro Yamashita, Toshihiro Imaeda, Toshio Tanaka, Jun Terauchi, Maki Miyamoto, Taiichi Ora, Michiko Tawada, Satoshi Endo, Shiro Takekawa, Asano Asami, Nobuhiro Suzuki, Yasutaka Nagisa, Yoshihide Nakano, Kaoru Watanabe, Hitomi Ogino,