Novel vasopressin V2 receptor-selective antagonists, pyrrolo[2,1-a]quinoxaline and pyrrolo[2,1-c][1,4]benzodiazepine derivatives

Bioorg Med Chem. 1999 Jun;7(6):1247-54. doi: 10.1016/s0968-0896(99)00049-8.

Abstract

The intent of the work was to study the structure-activity relationships of AVP receptor antagonists bearing a chiral ring as a partial structure since such studies had been reported for only achiral compounds. In the present paper, we deal with compounds consisting of the chiral tricyclic hetero ring (1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxaline and 1,2,3,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine) and 2-phenylbenzanilide analogues. These compounds exhibited a highly selective affinity for V2 receptor, and their stereochemical configuration had a great influence on V2 receptor binding. VP-343 (N-[4-[[(2S,3aR)-2-hydroxy-2,3,3a,4-tetrahydropyrrolo[1,2-a] quinoxalin-5(1H)-yl]carbonyl]phenyl]-4'-methyl[1,1'-biphenyl]-2-ca rboxamide), VP-365 (N-[4-[[(11aS)-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benz odiazepin-10(5H)-yl]carbonyl]phenyl][1,1'-biphenyl-2-carboxamide) and VP-339 (N-[4-[[(11aS)-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]+ ++benzodiazepin-10(5H)-yl]carbonyl]phenyl][1,1'-biphenyl]-2-carboxami de) were the most potent compounds in vitro and in vivo. The IC50 values of VP-343, VP-365 and VP-339 against V2 receptor were 0.772, 1.18 and 0.216 nM, respectively. The ED300 values (dose required to increase three times the urine volume of the control rats; oral administration) of VP-343, VP-365 and VP-339 were 0.22, 0.31 and 0.78 mg/kg, respectively.

MeSH terms

  • Animals
  • Antidiuretic Hormone Receptor Antagonists*
  • Benzodiazepines / chemical synthesis
  • Benzodiazepines / pharmacology*
  • Diuresis / drug effects
  • Diuretics / chemical synthesis*
  • Diuretics / pharmacology
  • In Vitro Techniques
  • Pyrroles / chemical synthesis
  • Pyrroles / pharmacology*
  • Quinoxalines / chemical synthesis
  • Quinoxalines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Vasopressins / drug effects
  • Vasopressins / metabolism

Substances

  • Antidiuretic Hormone Receptor Antagonists
  • Diuretics
  • Pyrroles
  • Quinoxalines
  • VP 339
  • VP 343
  • VP 365
  • Vasopressins
  • Benzodiazepines