5 research outputs found
DISCOVERY OF LFF571 AS AN INVESTIGATIONAL AGENT FOR Clostridium difficile INFECTION
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
Application of Virtual Screening to the Identification of New LpxC Inhibitor Chemotypes, Oxazolidinone and Isoxazoline
This report summarizes the identification and synthesis of novel LpxC inhibitors aided by computational methods that leveraged numerous crystal structures. This effort led to the identification of oxazolidinone and isoxazoline inhibitors with potent in vitro activity against P. aeruginosa and other Gram-negative bacteria. Representative compound 13f demonstrated efficacy against P. aeruginosa in a mouse neutropenic thigh infection model. The antibacterial activity against K. pneumoniae could be potentiated by Gram-positive antibiotics rifampicin (RIF) and vancomycin (VAN) in both in vitro and in vivo models
Optimization of novel monobactams with activity against carbapenem-resistant Enterobacteriaceae - Identification of LYS228
Metallo-β-lactamases (MBLs), such as New Delhi metallo-β-lactamase (NDM-1) have spread world-wide and present a serious threat. Expression of MBLs confers resistance in Gram-negative bacteria to all classes of β-lactam antibiotics, with the exception of monobactams, which are intrinsically stable to MBLs. However, existing first generation monobactam drugs like aztreonam have limited clinical utility against MBL-expressing strains because they are impacted by serine β-lactamases (SBLs), which are often co-expressed in clinical isolates. Here, we optimized novel monobactams for stability against SBLs, which led to the identification of LYS228 (compound 31). LYS228 is potent in the presence of all classes of β-lactamases and shows potent activity against carbapenem-resistant isolates of Enterobacteriaceae (CRE)
Potent Nonimmunosuppressive Cyclophilin Inhibitors With Improved Pharmaceutical Properties and Decreased Transporter Inhibition
Nonimmunosuppressive
cyclophilin inhibitors have demonstrated efficacy
for the treatment of hepatitis C infection (HCV). However, alisporivir,
cyclosporin A, and most other cyclosporins are potent inhibitors of
OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction
of the side chain hydrophobicity of the P4 residue preserves cyclophilin
binding and antiviral potency while decreasing transporter inhibition.
Representative inhibitor <b>33</b> (NIM258) is a less potent
transporter inhibitor relative to previously described cyclosporins,
retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic
profile in rats and dogs. An X-ray structure of <b>33</b> bound
to rat cyclophilin D is reported