Structure−Activity Relationships of 9-Substituted-9-Dihydroerythromycin-Based Motilin Agonists: Optimizing for Potency and Safety

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• 作者：Simon J. Shaw ; Yue Chen ; Hao Zheng ; Hong Fu ; Mark A. Burlingame ; Saul Marquez ; Yong Li ; Mark Claypool ; Christopher W. Carreras ; William Crumb ; Dwight J. Hardy ; David C. Myles ; Yaoquan Liu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：November 12, 2009
• 年：2009
• 卷：52
• 期：21
• 页码：6851-6859
• 全文大小：860K
• 年卷期：v.52,no.21(November 12, 2009)
• ISSN：1520-4804

文摘

A series of 9-dihydro-9-acetamido-N-desmethyl-N-isopropyl erythromycin A analogues and related derivatives was generated as motilin agonists. The compounds were optimized for potency while showing both minimal antibacterial activity and hERG inhibition. As the substituent on the amide was increased in lipophilicity the potency and hERG inhibition increased, while polar groups lowered potency, without significantly impacting hERG inhibition. The N-methyl acetamide 7a showed the optimal in vitro profile and was probed further by varying the chain length to the macrocycle as well as changing the macrocycle scaffold. 7a remained the compound with the best in vitro properties.