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Synthesis and SAR studies of novel benzodiazepinedione-based inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB).
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2018 Dec 15; Vol. 28 (23-24), pp. 3601-3605. Date of Electronic Publication: 2018 Oct 29. - Publication Year :
- 2018
-
Abstract
- Synthesis and structure-activity relationships (SAR) of a novel series of benzodiazepinedione-based inhibitors of Clostridium difficile toxin B (TcdB) are described. Compounds demonstrating low nanomolar affinity for TcdB, and which possess improved stability in mouse plasma vs. earlier compounds from this series, have been identified. Optimized compound 11d demonstrates a good pharmacokinetic (PK) profile in mouse and hamster and is efficacious in a hamster survival model of Clostridium difficile infection.<br /> (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Subjects :
- Administration, Oral
Animals
Anti-Bacterial Agents pharmacokinetics
Anti-Bacterial Agents therapeutic use
Bacterial Proteins metabolism
Bacterial Toxins metabolism
Benzodiazepines pharmacokinetics
Benzodiazepines therapeutic use
CHO Cells
Clostridioides difficile metabolism
Clostridium Infections drug therapy
Clostridium Infections veterinary
Cricetinae
Cricetulus
Half-Life
Mice
Structure-Activity Relationship
Anti-Bacterial Agents chemical synthesis
Bacterial Proteins antagonists & inhibitors
Bacterial Toxins antagonists & inhibitors
Benzodiazepines chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 28
- Issue :
- 23-24
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 30392779
- Full Text :
- https://doi.org/10.1016/j.bmcl.2018.10.047