Selective angiotensin II AT 2 receptor agonists with reduced CYP 450 inhibition

A. K. Mahalingam, Yiqian Wan, A. M.S. Murugaiah, Charlotta Wallinder, Xiongyu Wu, Bianca Plouffe, Milad Botros, Fred Nyberg, Anders Hallberg, Nicole Gallo-Payet*, Mathias Alterman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Structural alterations to the benzylic position of the first drug-like selective angiotensin II AT 2 receptor agonist (1) have been performed, with the emphasis to reduce the CYP 450 inhibitory property of the initial structure. The imidazole moiety, responsible for the CYP 450 inhibitory effect in 1, was replaced with various heterocycles. In addition, the modes of attachment of the heterocycles, that is, carbon versus nitrogen attachment, and introduction of carbonyl functionalities to the benzylic position have been evaluated. In all the three series, AT 2 receptor ligands with affinity in the lower nanomolar range were identified. None of the analogues, regardless of the substituents, exhibited any affinity for the AT 1 receptor. Compounds with substantially reduced inhibition of the CYP 450 enzymes were obtained. Among them the compound 60 was found to induce neurite elongation in NG 108-15 cells and served as potent AT 2 selective agonist.

Original languageEnglish
Pages (from-to)4570-4590
Number of pages21
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number12
DOIs
Publication statusPublished - 15 Jun 2010
Externally publishedYes

Keywords

  • Agonist
  • Angiotesin
  • AT

ASJC Scopus subject areas

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

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