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Title: Discovery of LFF571: An Investigational Agent for Clostridium difficile Infection

Abstract

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-activity 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.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »; ; ; ; ; ; ; ; ;  [1] « less
  1. (Novartis)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1049582
Resource Type:
Journal Article
Journal Name:
J. Med. Chem.
Additional Journal Information:
Journal Volume: 55; Journal Issue: (5) ; 03, 2012; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; ANIMALS; ANTIBIOTICS; CHEMISTRY; CLOSTRIDIUM; DEATH; DIARRHEA; DICARBOXYLIC ACIDS; DISEASE INCIDENCE; LARGE INTESTINE; MORTALITY; SOLUBILITY; TOXINS

Citation Formats

LaMarche, Matthew J., Leeds, Jennifer A., Amaral, Adam, Brewer, Jason T., Bushell, Simon M., Deng, Gejing, Dewhurst, Janetta M., Ding, Jian, Dzink-Fox, JoAnne, Gamber, Gabriel, Jain, Akash, Lee, Kwangho, Lee, Lac, Lister, Troy, McKenney, David, Mullin, Steve, Osborne, Colin, Palestrant, Deborah, Patane, Michael A., Rann, Elin M., Sachdeva, Meena, Shao, Jian, Tiamfook, Stacey, Trzasko, Anna, Whitehead, Lewis, Yifru, Aregahegn, Yu, Donghui, Yan, Wanlin, and Zhu, Qingming. Discovery of LFF571: An Investigational Agent for Clostridium difficile Infection. United States: N. p., 2012. Web. doi:10.1021/jm201685h.
LaMarche, Matthew J., Leeds, Jennifer A., Amaral, Adam, Brewer, Jason T., Bushell, Simon M., Deng, Gejing, Dewhurst, Janetta M., Ding, Jian, Dzink-Fox, JoAnne, Gamber, Gabriel, Jain, Akash, Lee, Kwangho, Lee, Lac, Lister, Troy, McKenney, David, Mullin, Steve, Osborne, Colin, Palestrant, Deborah, Patane, Michael A., Rann, Elin M., Sachdeva, Meena, Shao, Jian, Tiamfook, Stacey, Trzasko, Anna, Whitehead, Lewis, Yifru, Aregahegn, Yu, Donghui, Yan, Wanlin, & Zhu, Qingming. Discovery of LFF571: An Investigational Agent for Clostridium difficile Infection. United States. doi:10.1021/jm201685h.
LaMarche, Matthew J., Leeds, Jennifer A., Amaral, Adam, Brewer, Jason T., Bushell, Simon M., Deng, Gejing, Dewhurst, Janetta M., Ding, Jian, Dzink-Fox, JoAnne, Gamber, Gabriel, Jain, Akash, Lee, Kwangho, Lee, Lac, Lister, Troy, McKenney, David, Mullin, Steve, Osborne, Colin, Palestrant, Deborah, Patane, Michael A., Rann, Elin M., Sachdeva, Meena, Shao, Jian, Tiamfook, Stacey, Trzasko, Anna, Whitehead, Lewis, Yifru, Aregahegn, Yu, Donghui, Yan, Wanlin, and Zhu, Qingming. Fri . "Discovery of LFF571: An Investigational Agent for Clostridium difficile Infection". United States. doi:10.1021/jm201685h.
@article{osti_1049582,
title = {Discovery of LFF571: An Investigational Agent for Clostridium difficile Infection},
author = {LaMarche, Matthew J. and Leeds, Jennifer A. and Amaral, Adam and Brewer, Jason T. and Bushell, Simon M. and Deng, Gejing and Dewhurst, Janetta M. and Ding, Jian and Dzink-Fox, JoAnne and Gamber, Gabriel and Jain, Akash and Lee, Kwangho and Lee, Lac and Lister, Troy and McKenney, David and Mullin, Steve and Osborne, Colin and Palestrant, Deborah and Patane, Michael A. and Rann, Elin M. and Sachdeva, Meena and Shao, Jian and Tiamfook, Stacey and Trzasko, Anna and Whitehead, Lewis and Yifru, Aregahegn and Yu, Donghui and Yan, Wanlin and Zhu, Qingming},
abstractNote = {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-activity 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.},
doi = {10.1021/jm201685h},
journal = {J. Med. Chem.},
issn = {0022-2623},
number = (5) ; 03, 2012,
volume = 55,
place = {United States},
year = {2012},
month = {11}
}