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 Rodents

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• 作者：Brian M. Fox ; Kazuyuki Sugimoto ; Kiyosei Iio ; Atsuhito Yoshida ; Jian (Ken) Zhang ; Kexue Li ; Xiaolin Hao ; Marc Labelle ; Marie-Louise Smith ; Steven M. Rubenstein ; Guosen Ye ; Dustin McMinn ; Simon Jackson ; Rebekah Choi ; Bei Shan ; Ji Ma ; Shichang Miao ; Takuya Matsui ; Nobuya Ogawa ; Masahiro Suzuki ; Akio Kobayashi ; Hidekazu Ozeki ; Chihiro Okuma ; Yukihito Ishii ; Daisuke Tomimoto ; Noboru Furakawa ; Masahiro Tanaka ; Mutsuyoshi Matsushita ; Mitsuru Takahashi ; Takashi Inaba ; Shoichi Sagawa ; Frank Kayser
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 24, 2014
• 年：2014
• 卷：57
• 期：8
• 页码：3464-3483
• 全文大小：785K
• 年卷期：v.57,no.8(April 24, 2014)
• ISSN：1520-4804

文摘

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 was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane 42, which displayed significantly improved DGAT1 inhibition compared to 1. Spiroindane 42 was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies.