Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd.,1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Eur J Med Chem. 2011 May;46(5):1892-6. doi: 10.1016/j.ejmech.2011.02.002. Epub 2011 Feb 26.
Expansion of the 6-membered ring and subsequent fine-tuning of the newly obtained 7-membered spiropiperidine structure resulted in the discovery of a series of novel and potent SCD1 inhibitors. Preliminary SAR was explored by modifying an alkyl chain on the azepine nitrogen and resulted in the identification of a highly potent SCD1 inhibitor: 6-[5-(cyclopropylmethyl)-4,5-dihydro-1'H,3H-spiro[1,5-benzoxazepine-2,4'-piperidin]-1'-yl]-N-(2-hydroxy-2-pyridin-3-ylethyl)pyridazine-3-carboxamide (9). Compound 9 exhibited an IC(50) value of 0.01 μM against human SCD1.
通过扩展六元环并对新获得的七元螺哌啶结构进行精细调整，发现了一系列新型强效 SCD1 抑制剂。通过修饰氮上的氮杂环庚烷上的烷基链来探索初步的 SAR，从而确定了一种高效的 SCD1 抑制剂：6-[5-(环丙甲基)-4,5-二氢-1'H,3H-螺[1,5-苯并恶嗪-2,4'-哌啶]-1'-基]-N-(2-羟基-2-吡啶-3-基乙基)哒嗪-3-甲酰胺（9）。化合物 9 对人 SCD1 的 IC50 值为 0.01 μM。
