Lamarche, Matthew, Leeds, Jennifer, Amaral, Adam, Brewer, Jason, Bushell, Simon, Ding, Jian, Dzink-Fox, Joann, Gamber, Gabriel, Jain, Akash, Lee, Kwangho, Lister, Troy, Mckenney, David, Mullin, Steve, Osborne, Colin, Palestrant, Deborah, Patane, Michael, Rann, Elin, Sachdeva, Meena, Shao, Jian, Tiamfook, Stacey, Williams, Anna, Whitehead, Lewis, Yifru, Aregahegn, Yu, Donghui, 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

Abstract

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.

Item Type:	Article
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
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Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
Date Deposited:	13 Oct 2015 13:14
Last Modified:	13 Oct 2015 13:14
URI:	https://oak.novartis.com/id/eprint/6284