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.
Keywords:
Benzodiazepinedione; Clostridium difficile; Inhibitor; TcdB; Toxin.
Copyright © 2018 Elsevier Ltd. All rights reserved.
MeSH terms
-
Administration, Oral
-
Animals
-
Anti-Bacterial Agents / chemical synthesis*
-
Anti-Bacterial Agents / pharmacokinetics
-
Anti-Bacterial Agents / therapeutic use
-
Bacterial Proteins / antagonists & inhibitors*
-
Bacterial Proteins / metabolism
-
Bacterial Toxins / antagonists & inhibitors*
-
Bacterial Toxins / metabolism
-
Benzodiazepines / chemistry*
-
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
Substances
-
Anti-Bacterial Agents
-
Bacterial Proteins
-
Bacterial Toxins
-
toxB protein, Clostridium difficile
-
Benzodiazepines