19-Hydroxyeicosatetraenoic acid analogs: Antagonism of 20-hydroxyeicosatetraenoic acid-induced vascular sensitization and hypertension

Bioorg Med Chem Lett. 2019 Oct 1;29(19):126616. doi: 10.1016/j.bmcl.2019.08.020. Epub 2019 Aug 13.

Abstract

19-Hydroxyeicosatetraenoic acid (19-HETE, 1), a metabolically and chemically labile cytochrome P450 eicosanoid, has diverse biological activities including antagonism of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE, 2). A SAR study was conducted to develop robust analogs of 1 with improved in vitro and in vivo efficacy. Analogs were screened in vitro for inhibition of 20-HETE-induced sensitization of rat renal preglomerular microvessels toward phenylephrine and demonstrated to normalize the blood pressure of male Cyp4a14(-/-) mice that display androgen-driven, 20-HETE-dependent hypertension.

Keywords: Antagonist; Bioisosteric replacement; Eicosanoid; Hypertension; Vascular sensitization.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antihypertensive Agents / chemistry*
  • Antihypertensive Agents / pharmacology*
  • Cytochrome P450 Family 4 / physiology*
  • Hydroxyeicosatetraenoic Acids / toxicity
  • Hypertension / chemically induced
  • Hypertension / drug therapy*
  • Hypertension / pathology
  • Kidney Glomerulus / blood supply
  • Kidney Glomerulus / drug effects*
  • Male
  • Mice
  • Mice, Knockout
  • Microvessels / drug effects*
  • Phenylephrine / toxicity
  • Vasoconstrictor Agents / toxicity

Substances

  • Antihypertensive Agents
  • Cyp4a14 protein, mouse
  • Hydroxyeicosatetraenoic Acids
  • Vasoconstrictor Agents
  • Phenylephrine
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Cytochrome P450 Family 4