Discovery of novel SCD1 inhibitors: 5-Alkyl-4,5-dihydro-3H-spiro[1,5-benzoxazepine-2,4′-piperidine] analogs

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 IC50 value of 0.01 μM against human SCD1.

Graphical abstractExpansion of the 6-membered ring and subsequent fine-tuning of the newly obtained 7-membered spiropiperidine structure resulted in the discovery of novel and potent SCD1 inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Expansion of the 6-membered ring resulted in the discovery of novel SCD1 inhibitors. ► Preliminary SAR resulted in the identification of a highly potent SCD1 inhibitor. ► Compound 9 exhibited an IC50 value of 0.01 μM against human SCD1.