The optimization of pyridazinone series of glucan synthase inhibitors

Bioorg Med Chem Lett. 2012 Aug 15;22(16):5268-71. doi: 10.1016/j.bmcl.2012.06.091. Epub 2012 Jul 4.

Abstract

A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model.

MeSH terms

  • Animals
  • Antifungal Agents / chemistry*
  • Antifungal Agents / pharmacokinetics
  • Antifungal Agents / therapeutic use
  • Candida / drug effects
  • Candidiasis / drug therapy
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / therapeutic use
  • Glucosyltransferases / antagonists & inhibitors*
  • Glucosyltransferases / metabolism
  • Half-Life
  • Mice
  • Microbial Sensitivity Tests
  • Pyridazines / chemistry*
  • Pyridazines / pharmacokinetics
  • Pyridazines / therapeutic use
  • Rats
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / therapeutic use

Substances

  • Antifungal Agents
  • Enzyme Inhibitors
  • Pyridazines
  • Sulfonamides
  • Glucosyltransferases
  • glucan synthase