Discovery of 6-phenylpyrimido [4, 5-b][1, 4] oxazines as potent and selective acyl CoA: diacylglycerol acyltransferase 1 (DGAT1) inhibitors with in vivo efficacy in …

…, M Labelle, ML Smith, SM Rubenstein…

文献索引：Fox, Brian M.; Sugimoto, Kazuyuki; Iio, Kiyosei; Yoshida, Atsuhito; Zhang, Jian; Li, Kexue; Hao, Xiaolin; Labelle, Marc; Smith, Marie-Louise; Rubenstein, Steven M.; Ye, Guosen; McMinn, Dustin; Jackson, Simon; Choi, Rebekah; Shan, Bei; Ma, Ji; Miao, Shichang; Matsui, Takuya; Ogawa, Nobuya; Suzuki, Masahiro; Kobayashi, Akio; Ozeki, Hidekazu; Okuma, Chihiro; Ishii, Yukihito; Tomimoto, Daisuke; Furakawa, Noboru; Tanaka, Masahiro; Matsushita, Mutsuyoshi; Takahashi, Mitsuru; Inaba, Takashi; Sagawa, Shoichi; Kayser, Frank Journal of Medicinal Chemistry, 2014 , vol. 57, # 8 p. 3464 - 3483

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被引用次数: 14

摘要

The discovery and optimization of a series of acyl CoA: diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido [4, 5-b][1, 4] oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid 1, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of 1 was observed that ...