Nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors: synthesis and pharmacological properties of 2-phenyl-4'-(2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carbonyl) benzanilide derivatives

Chem Pharm Bull (Tokyo). 1998 Oct;46(10):1566-79. doi: 10.1248/cpb.46.1566.

Abstract

A series of compounds structurally related to 2-phenyl-4'-(2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carbonyl) benzanilide was synthesized and demonstrated to have arginine vasopressin (AVP) antagonist activity for both V1A and V2 receptors. The introduction of a hydrophilic substituent group into the 5-position of the benzodiazepine ring resulted in an increase in oral availability. Especially, the (3-pyridyl)methyl (31b), the 2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl (32i), and the 2-(4-methylpiperazin-1-yl)ethyl (33g) derivatives exhibited high antagonist activities and high oral availability. Details of the synthesis and pharmacological properties of this series are presented.

MeSH terms

  • Anilides / chemical synthesis*
  • Anilides / pharmacokinetics
  • Anilides / pharmacology
  • Animals
  • Antidiuretic Hormone Receptor Antagonists*
  • Arginine Vasopressin / antagonists & inhibitors*
  • Biological Availability
  • Female
  • In Vitro Techniques
  • Indoles / chemical synthesis*
  • Indoles / pharmacokinetics
  • Indoles / pharmacology
  • Magnetic Resonance Spectroscopy
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / pharmacokinetics
  • Pyrrolidines / pharmacology
  • Rabbits
  • Rats
  • Receptors, Oxytocin / drug effects
  • Receptors, Oxytocin / metabolism

Substances

  • Anilides
  • Antidiuretic Hormone Receptor Antagonists
  • Indoles
  • Pyrrolidines
  • Receptors, Oxytocin
  • Arginine Vasopressin
  • relcovaptan