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

Charlotta Wallinder; Christian Sköld; Milad Botros; Marie-Odile Guimond; Mathias Hallberg; Nicole Gallo-Payet; Anders Karlén; Mathias Alterman

doi:10.1021/ml500427r

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. eCollection 2015 Feb 12.

Authors

Charlotta Wallinder¹, Christian Sköld¹, Milad Botros², Marie-Odile Guimond³, Mathias Hallberg², Nicole Gallo-Payet³, Anders Karlén¹, Mathias Alterman¹

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.

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.