Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
J Med Chem. 2014 Apr 24;57(8):3464-83. doi: 10.1021/jm500135c. Epub 2014 Apr 8.
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.
本文描述了基于嘧啶并[4,5-b][1,4]恶嗪骨架的酰基辅酶 A：二酰基甘油酰基转移酶 1（DGAT1）抑制剂的发现和优化。对具有中等活性的高内涵筛选命中化合物的 SAR 进行了研究，发现了苯环己基乙酸 1，其显示出良好的 DGAT1 抑制活性、选择性和 PK 性质。在临床前毒性研究中观察到 1 的一种代谢物，该代谢物负责升高肝酶 ALT 和 AST 的水平。随后，合成了类似物以阻止有毒代谢物的形成。这一努力导致发现了螺吲哚烷 42，其与 1 相比，对 DGAT1 的抑制作用显著提高。螺吲哚烷 42 在体内的啮齿动物中耐受性良好，在小鼠口服甘油三酯摄取研究中显示出疗效，并且在临床前毒性研究中具有可接受的安全性特征。
