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Lamarche, Matthew and Leeds, Jennifer and Amaral, Adam and Brewer, Jason and Bushell, Simon and Ding, Jian and Dzink-Fox, Joann and Gamber, Gabriel and Jain, Akash and Lee, Kwangho and Lister, Troy and Mckenney, David and Mullin, Steve and Osborne, Colin and Palestrant, Deborah and Patane, Michael and Rann, Elin and Sachdeva, Meena and Shao, Jian and Tiamfook, Stacey and Williams, Anna and Whitehead, Lewis and Yifru, Aregahegn and Yu, Donghui and Yan, Wanlin and Zhu, Qingming (2012) DISCOVERY OF LFF571 AS AN INVESTIGATIONAL AGENT FOR Clostridium difficile INFECTION. Journal of Medicinal Chemistry, 55 (5). pp. 2376-2387. ISSN 0022-2623


Clostridium difficile is a Gram positive, spore-forming, anaerobic bacterium which 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. The prevalence and severity of C. difficile infection are increasing, causing increased morbidity and mortality. 4-Aminothiazolyl analogs of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of serious Gram positive bacterial infections, including C. difficile infection. Optimization of the 4-aminothiazolyl-natural product template focused on improving aqueous solubility over the natural product and previous development candidates (2, 3), and improving in vitro and in vivo antibacterial activity. Structure-activity relationships, structure-solubility relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies culminated in the identification of a dicarboxylic acid chemical series, which enhanced the solubility/efficacy profile by several orders of magnitude as compared to previous monoacid-based development candidates and led to the selection of LFF571 (4) as an investigational new drug for the treatment of C. difficile infection.

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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14


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