Optimization of N'-(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT6 antagonistic binding pocket

Bioorg Med Chem Lett. 2016 Mar 15;26(6):1605-1611. doi: 10.1016/j.bmcl.2016.02.001. Epub 2016 Feb 2.

Abstract

The discovery of non-basic N'-(arylsulfonyl)pyrazoline-1-carboxamidines as 5-HT6 antagonists with unique structural features was recently disclosed. Here we describe how this structural class was further developed by addressing an unexplored interaction site of the 5-HT6 receptor. Compound 13 resulting from this effort is a highly potent and selective 5-HT6 antagonist with improved metabolic stability. It is furthermore devoid of hERG affinity. Despite its modest CNS/plasma ratio, a high brain free fraction ensured substantial exposure to allow for rodent cognition studies.

Keywords: 5-HT(6) receptor; Molecular modeling; Non-basic 5-HT(6) antagonists; N′-(Arylsulfonyl)pyrazoline-1-carboxamidines.

MeSH terms

  • Binding Sites / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Receptors, Serotonin / metabolism*
  • Serotonin Antagonists / chemical synthesis
  • Serotonin Antagonists / chemistry
  • Serotonin Antagonists / pharmacology*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Pyrazoles
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Sulfonamides
  • serotonin 6 receptor