Synthesis, vasorelaxant activity and antihypertensive effect of benzo[d]imidazole derivatives

Bioorg Med Chem. 2010 Jun 1;18(11):3985-91. doi: 10.1016/j.bmc.2010.04.027. Epub 2010 Apr 14.

Abstract

A series of 1H-benzo[d]imidazole analogues of Pimobendan, substituted at position 5 with either -CF(3) or -NO(2), were synthesized using a short synthetic route. All the nitro derivatives were potent, and exhibited a concentration- and partial endothelium-dependent vasorelaxant effects, with EC(50)s <5microM. 2-Methoxy-4-[5-nitro-1H-benzo[d]imidazol-2-yl]phenol (compound 13) was the most potent derivative of the series, showing an EC(50) value of 1.81microM and E(max) of 91.7% for ex vivo relaxant response in intact aortic rings, resulting in a 2.5-fold higher activity compared to Pimobendan. The closely related 5-CF(3) analogue (compound 8), was 19 times less potent than 13. The antihypertensive activity of compound 13 was evaluated at doses of 25, 50 and 100mgkg(-1), using spontaneously hypertensive rats (SHR), showing a statistically significant dose-dependent effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antihypertensive Agents / chemical synthesis*
  • Antihypertensive Agents / pharmacology
  • Aorta / drug effects
  • Dose-Response Relationship, Drug
  • Imidazoles / chemical synthesis*
  • Imidazoles / pharmacology
  • Pyridazines
  • Rats
  • Rats, Inbred SHR
  • Structure-Activity Relationship
  • Vasodilator Agents / chemical synthesis*
  • Vasodilator Agents / pharmacology

Substances

  • Antihypertensive Agents
  • Imidazoles
  • Pyridazines
  • Vasodilator Agents
  • pimobendan