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

Rambabu Dakarapu, Ramu Errabelli, Vijaya L. Manthati, Adeniyi Michael Adebesin, Deb K. Barma, Deepan Barma, Victor Garcia, Fan Zhang, Michal Laniado Schwartzman, J R Falck

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number126616
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number19
DOIs
StatePublished - Oct 1 2019

Keywords

  • Antagonist
  • Bioisosteric replacement
  • Eicosanoid
  • Hypertension
  • QDEGARKRKXEQDF-AAHZGTINSA-M
  • Vascular sensitization

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Dakarapu, R., Errabelli, R., Manthati, V. L., Michael Adebesin, A., Barma, D. K., Barma, D., Garcia, V., Zhang, F., Laniado Schwartzman, M., & Falck, J. R. (2019). 19-Hydroxyeicosatetraenoic acid analogs: Antagonism of 20-hydroxyeicosatetraenoic acid-induced vascular sensitization and hypertension. Bioorganic and Medicinal Chemistry Letters, 29(19), [126616]. https://doi.org/10.1016/j.bmcl.2019.08.020