Discovery of LFF571: an investigational agent for Clostridium difficile infection.
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.
Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. matthew.lamarche@novartis.com
Matthew J
MJ
LaMarche
Jennifer A
JA
Leeds
Adam
A
Amaral
Jason T
JT
Brewer
Simon M
SM
Bushell
Gejing
G
Deng
Janetta M
JM
Dewhurst
Jian
J
Ding
JoAnne
J
Dzink-Fox
Gabriel
G
Gamber
Akash
A
Jain
Kwangho
K
Lee
Lac
L
Lee
Troy
T
Lister
David
D
McKenney
Steve
S
Mullin
Colin
C
Osborne
Deborah
D
Palestrant
Michael A
MA
Patane
Elin M
EM
Rann
Meena
M
Sachdeva
Jian
J
Shao
Stacey
S
Tiamfook
Anna
A
Trzasko
Lewis
L
Whitehead
Aregahegn
A
Yifru
Donghui
D
Yu
Wanlin
W
Yan
Qingming
Q
Zhu
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016360:Clostridioides difficile / Q000187:drug effects*; D006224:Cricetinae; D018360:Crystallography, X-Ray; D016983:Enterococcus / Q000187:drug effects; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D005260:Female; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D010444:Peptide Elongation Factor Tu / Q000037:antagonists & inhibitors / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013211:Staphylococcus aureus / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D014867:Water; D010456:Peptides, Cyclic
D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D010444:Peptide Elongation Factor Tu; D013844:Thiazoles; D014867:Water; C573298:LFF571; D010456:Peptides, Cyclic