1. 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
- Author
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Masahiro Suzuki, Akio Kobayashi, Mitsuru Takahashi, Steven M. Rubenstein, Takuya Matsui, Bei Shan, Kazuyuki Sugimoto, Marie-Louise Smith, Xiaolin Hao, Kexue Li, Yukihito Ishii, Masahiro Tanaka, Jian Ken Zhang, Frank Kayser, Mutsuyoshi Matsushita, Takashi Inaba, Rebekah Choi, Shoichi Sagawa, Nobuya Ogawa, Daisuke Tomimoto, Hidekazu Ozeki, Marc Labelle, Guosen Ye, Atsuhito Yoshida, Chihiro Okuma, Kiyosei Iio, Simon Jackson, Shichang Miao, Brian M. Fox, Noboru Furakawa, Dustin McMinn, and Ji Ma
- Subjects
Metabolite ,Oxazines ,Pharmacology ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,Acyl-CoA ,chemistry.chemical_compound ,Dogs ,In vivo ,Drug Discovery ,Animals ,Structure–activity relationship ,Aspartate Aminotransferases ,Diacylglycerol O-Acyltransferase ,Enzyme Inhibitors ,Triglycerides ,chemistry.chemical_classification ,Triglyceride ,Drug discovery ,Alanine Transaminase ,Macaca mulatta ,High-Throughput Screening Assays ,Rats ,Mice, Inbred C57BL ,chemistry ,Biochemistry ,Molecular Medicine ,Diacylglycerol Acyltransferase - Abstract
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.
- Published
- 2014