New V1a receptor antagonist. Part 1. Synthesis and SAR development of urea derivatives

Bioorg Med Chem Lett. 2020 Sep 15;30(18):127416. doi: 10.1016/j.bmcl.2020.127416. Epub 2020 Jul 24.

Abstract

Solid preclinical evidence links vasopressin to social behavior in animals, so, extensive work has been initiated to find new vasopressin V1a receptor antagonists which can improve deteriorated social behavior in humans and can treat the core symptoms of autistic behavior, as well. Our aim was to identify new chemical entities with antagonizing effects on vasopressin V1a receptors. Starting from a moderately potent HTS hit (7), we identified a molecule (49) having nanomolar binding strength and functional activity, which is in the same range as the potency of clinically tested V1a antagonists.

Keywords: Antagonist; HTS; Synthesis; Tetrahydroquinazolines; V1a; Vasopressin.

MeSH terms

  • Antidiuretic Hormone Receptor Antagonists / chemical synthesis*
  • Antidiuretic Hormone Receptor Antagonists / pharmacology
  • High-Throughput Screening Assays
  • Humans
  • Inhibitory Concentration 50
  • Piperazine / chemistry
  • Protein Binding
  • Pyridines / chemistry
  • Quinolines / chemistry
  • Receptors, Vasopressin / metabolism*
  • Social Behavior Disorders / drug therapy*
  • Structure-Activity Relationship
  • Urea / chemical synthesis*
  • Urea / pharmacology

Substances

  • Antidiuretic Hormone Receptor Antagonists
  • Pyridines
  • Quinolines
  • Receptors, Vasopressin
  • Piperazine
  • Urea
  • 1,2,3,4-tetrahydroquinoline