Comparison of 3D structures and AT(1) binding properties of pyrazolidine-3,5-diones and tetrahydropyridazine-3,6-diones with parent antihypertensive drug irbesartan

J Med Chem. 2002 Oct 10;45(21):4794-8. doi: 10.1021/jm010457z.

Abstract

A new series of nonpeptide AT(1) receptor antagonists were recently developed, based on the structure of irbesartan (Le Bourdonnec et al. J. Med. Chem. 2000, 43, 2685-2697). The lead compound 1 displayed high selectivity for the AT(1) receptor subtype but lower binding affinity than irbesartan. As expected from molecular modeling studies, extension of the pyrazolidine-3,5-dione scaffold to the six-membered heterocycle tetrahydropyridazine-3,6-dione led to an enhancement of the binding affinity toward the AT(1) receptor.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / metabolism*
  • Angiotensin Receptor Antagonists
  • Antihypertensive Agents / chemistry*
  • Antihypertensive Agents / pharmacology
  • Biphenyl Compounds / chemistry*
  • Biphenyl Compounds / pharmacology
  • Crystallography, X-Ray
  • Humans
  • Irbesartan
  • Models, Molecular
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology
  • Pyridazines / chemistry*
  • Pyridazines / pharmacology
  • Receptor, Angiotensin, Type 1
  • Receptors, Angiotensin / chemistry*
  • Receptors, Angiotensin / metabolism
  • Structure-Activity Relationship
  • Tetrazoles / chemistry*
  • Tetrazoles / pharmacology
  • Tumor Cells, Cultured

Substances

  • Angiotensin Receptor Antagonists
  • Antihypertensive Agents
  • Biphenyl Compounds
  • Pyrazoles
  • Pyridazines
  • Receptor, Angiotensin, Type 1
  • Receptors, Angiotensin
  • Tetrazoles
  • Angiotensin II
  • Irbesartan