Development of a Liver-Targeted Stearoyl-CoA Desaturase (SCD) Inhibitor (MK-8245) to Establish a Therapeutic Window for the Treatment of Diabetes and Dyslipidemia

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• 作者：Renata M. Oballa ; Liette Belair ; W. Cameron Black ; Kelly Bleasby ; Chi Chung Chan ; Carole Desroches ; Xiaobing Du ; Robert Gordon ; Jocelyne Guay ; Sebastien Guiral ; Michael J. Hafey ; Emelie Hamelin ; Zheng Huang ; Brian Kennedy ; Nicolas Lachance ; France Landry ; Chun Sing Li ; Joseph Mancini ; Denis Normandin ; Alessandro Pocai ; David A. Powell ; Yeeman K. Ramtohul ; Kathryn Skorey ; Dan S酶rensen ; Wayne Sturkenboom ; Angela Styhler ; Deena M. Waddleton ; Hao Wang ; Simon Wong ; Lijing Xu ; Lei Zhang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 28, 2011
• 年：2011
• 卷：54
• 期：14
• 页码：5082-5096
• 全文大小：1200K
• 年卷期：v.54,no.14(July 28, 2011)
• ISSN：1520-4804

文摘

The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.