Discovery of liver-targeted inhibitors of stearoyl-CoA desaturase (SCD1)

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• 作者：Yongqi Deng^a ; ^{yongqi.deng@merck.com} ; Zhiwei Yang^a ; ^&dagger ; ; Gerald W. Shipps Jr.^a ; ^&Dagger ; ; Sie-Mun Lo^a ; Robert West^b ; Joyce Hwa^c ; Shuqin Zheng^c ; Constance Farley^b ; Jean Lachowicz^b ; ^§ ; ; Margaret van Heek^c ; Alan S. Bass^b ; Dinesh P. Sinha^b ; Craig R. Mahon^c ; Mark E. Cartwright^b
• 关键词：Stearoyl-coenzyme A desaturase 1 ; Spirocyclic oxazepine ; Liver-targeted inhibitors ; Saturated fatty acids ; Unsaturated fatty acids
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 February, 2013
• 年：2013
• 卷：23
• 期：3
• 页码：791-796
• 全文大小：2761 K

文摘

Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies.