Discovery of LFF571: An Investigational Agent for Clostridium difficile Infection

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• 作者：Matthew J. LaMarche ; Jennifer A. Leeds ; Adam Amaral ; Jason T. Brewer ; Simon M. Bushell ; Gejing Deng ; Janetta M. Dewhurst ; Jian Ding ; JoAnne Dzink-Fox ; Gabriel Gamber ; Akash Jain ; Kwangho Lee ; Lac Lee ; Troy Lister ; David McKenney ; Steve Mullin ; Colin Osborne ; Deborah Palestrant ; Michael A. Patane ; Elin M. Rann ; Meena Sachdeva ; Jian Shao ; Stacey Tiamfook ; Anna Trzasko ; Lewis Whitehead ; Aregahegn Yifru ; Donghui Yu ; Wanlin Yan ; Qingming Zhu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：2376-2387
• 全文大小：529K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

Clostridium difficile (C. difficile) is a Gram positive, anaerobic bacterium that infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. Alarmingly, the prevalence and severity of C. difficile infection are increasing; thus, associated morbidity and mortality rates are rising. 4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of C. difficile infection. The medicinal chemistry effort focused on enhancing aqueous solubility relative to that of the natural product and previous development candidates (2, 3) and improving antibacterial activity. Structure鈥揳ctivity relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies identified a series of dicarboxylic acid derivatives, which enhanced solubility/efficacy profile by several orders of magnitude compared to previously studied compounds and led to the selection of LFF571 (4) as an investigational new drug for treating C. difficile infection.