Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Bioorg Med Chem. 2021 Apr 1;35:116056. doi: 10.1016/j.bmc.2021.116056. Epub 2021 Feb 14.
A structure-activity relationship (SAR) study towards novel ACC1-selective inhibitors was carried out by modifying the molecular length of the linker in biaryl derivative 1 g, an ACC1/2 dual inhibitor. Ultimately, this leads us to discover novel phenoxybenzyloxy derivative 1i as a potent ACC1-selective inhibitor. Further chemical modification of this scaffold to improve cellular potency as well as physicochemical and pharmacokinetic (PK) properties produced N-2-(pyridin-2-ylethyl)acetamide derivative 1n, which showed highly potent ACC1-selective inhibition as well as sufficient PK profile for further in vivo evaluations. Oral administration of 1n significantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at doses of 100 mg/kg. Accordingly, our novel series of potent ACC1-selective inhibitors represents a set of useful orally-available research tools, as well as potential therapeutic agents for cancer and fatty acid-related diseases.
我们对双靶点乙酰辅酶 A 羧化酶 1/2（ACC1/2）抑制剂 1g 中的连接子分子长度进行了结构活性关系（SAR）研究，以此来开发新型的 ACC1 选择性抑制剂。最终，我们发现了新型的酚氧基苯氧甲基衍生物 1i，它是一种强效的 ACC1 选择性抑制剂。对该骨架结构进行进一步的化学修饰以提高细胞效力以及改善理化和药代动力学（PK）性质，得到了 N-2-（吡啶-2-基乙基）乙酰胺衍生物 1n，它表现出强效的 ACC1 选择性抑制作用以及足够的 PK 特性，可进一步进行体内评估。以 100mg/kg 的剂量口服给予 1n 可显著降低 HCT-116 异种移植肿瘤中丙二酰辅酶 A 的浓度。因此，我们新型的强效 ACC1 选择性抑制剂系列代表了一组有用的可口服的研究工具，以及用于癌症和脂肪酸相关疾病的潜在治疗剂。
