Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Bioorg Med Chem. 2019 Jun 15;27(12):2521-2530. doi: 10.1016/j.bmc.2019.03.023. Epub 2019 Mar 12.
We initiated our structure-activity relationship (SAR) studies for novel ACC1 inhibitors from 1a as a lead compound. Our initial SAR studies of 1H-Pyrrolo[3,2-b]pyridine-3-carboxamide scaffold revealed the participation of HBD and HBA for ACC1 inhibitory potency and identified 1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide derivative 1c as a potent ACC1 inhibitor. Although compound 1c had physicochemical and pharmacokinetic (PK) issues, we investigated the 1H-pyrrolo[3,2-b]pyridine core scaffold to address these issues. Accordingly, this led us to discover a novel 1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide derivative 1k as a promising ACC1 inhibitor, which showed potent ACC1 inhibition as well as sufficient cellular potency. Since compound 1k displayed favorable bioavailability in mouse cassette dosing PK study, we conducted in vivo Pharmacodynamics (PD) studies of this compound. Oral administration of 1k significantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at a dose of 100 mg/kg. Accordingly, our novel series of potent ACC1 inhibitors represent useful orally-available research tools, as well as potential therapeutic agents for cancer and fatty acid related diseases.
我们从先导化合物 1a 出发，开始了新型 ACC1 抑制剂的结构-活性关系（SAR）研究。我们对 1H-吡咯并[3,2-b]吡啶-3-甲酰胺骨架的初步 SAR 研究表明，HBD 和 HBA 参与了 ACC1 的抑制活性，并确定 1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺衍生物 1c 是一种有效的 ACC1 抑制剂。尽管化合物 1c 存在理化性质和药代动力学（PK）问题，但我们研究了 1H-吡咯并[3,2-b]吡啶核心骨架以解决这些问题。因此，这导致我们发现了一种新型的 1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺衍生物 1k，它是一种很有前途的 ACC1 抑制剂，具有很强的 ACC1 抑制作用和足够的细胞活性。由于化合物 1k 在小鼠盒式剂量 PK 研究中表现出良好的生物利用度，我们对该化合物进行了体内药效学（PD）研究。1k 的口服给药以 100mg/kg 的剂量显著降低了 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 抑制剂系列代表了有用的口服可用的研究工具，以及用于癌症和脂肪酸相关疾病的潜在治疗剂。
