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Novel acyl coenzyme A (CoA): Diacylglycerol acyltransferase-1 inhibitors: Synthesis and biological activities of diacylethylenediamine derivatives |
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| Authors: | Yoshihisa Nakada Thomas D. Aicher Yvan Le Huerou Timothy Turner Scott A. Pratt Stephen S. Gonzales Steve A. Boyd Hiroshi Miki Toshihiro Yamamoto Hiroshi Yamaguchi Koki Kato Shuji Kitamura |
| Affiliation: | 1. Medicinal Chemistry Research Laboratories, Takeda Pharmaceutical Company Ltd, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan;2. Discovery Research Center, Takeda Pharmaceutical Company Ltd, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan;3. Pharmacology Research Laboratories, Takeda Pharmaceutical Company Ltd, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan;4. Strategic Research Planning Department, Takeda Pharmaceutical Company Ltd, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan;5. Array Biopharma Inc, 3200 Walnut Street, Boulder, CO 80301, United States |
| Abstract: | A series of diacylethylenediamine derivatives were synthesized and evaluated for their inhibitory activity against DGAT-1 and pharmacokinetic profile to discover new small molecule DGAT-1 inhibitors. Among the compounds, N-[2-({[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)ethyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 3x showed potent inhibitory activity and excellent PK profile. Oral administration of 3x to mice with dietary-induced obesity resulted in reduced body weight gain and white adipose tissue weight. |
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