Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT2 Receptor Ligands

  • ACS Med Chem Lett. 2014 Dec 8;6(2):178-82. doi: 10.1021/ml500427r.
Charlotta Wallinder  1 ,  Christian Sköld  1 ,  Milad Botros  2 ,  Marie-Odile Guimond  3 ,  Mathias Hallberg  2 ,  Nicole Gallo-Payet  3 ,  Anders Karlén  1 ,  Mathias Alterman  1
Affiliations
  • 1. Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala University , SE-751 23 Uppsala, Sweden.
  • 2. Beijer Laboratory, Department of Pharmaceutical Biosciences, BMC, Uppsala University SE-751 23 Uppsala, Sweden.
  • 3. Service of Endocrinology, Faculty of Medicine and Heath Sciences, University of Sherbrooke , Sherbrooke J1H 5N4, Quebec, Canada.
PMID: 25699147 DOI: 10.1021/ml500427r
Abstract

Migration of the methylene imidazole side chain in the first reported selective drug-like AT2 Receptor Agonist C21/M024 (1) delivered the AT2 Receptor Antagonist C38/M132 (2). We now report that the AT2 Receptor Antagonist compound 4, a biphenyl derivative that is structurally related to 2, is transformed to the agonist 6 by migration of the isobutyl group. The importance of the relative position of the methylene imidazole and the isobutyl substituent is highlighted herein.

Keywords
AT2 receptor; C21/M024; C38/M132; agonist; antagonist; nonpeptide ligands.