Open AccessA Series of Analogues to the AT 2 R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode
Author(s) -
Isaksson Rebecka,
Lindman Jens,
Wannberg Johan,
Sallander Jessica,
Backlund Maria,
Baraldi Dhaniel,
Widdop Robert,
Hallberg Mathias,
Åqvist Johan,
Gutierrez de Teran Hugo,
Gising Johan,
Larhed Mats
Publication year - 2019
Publication title -
chemistryopen
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.644
H-Index - 29
ISSN - 2191-1363
DOI - 10.1002/open.201800282
Subject(s) - antagonist , microsome , chemistry , stereochemistry , ligand (biochemistry) , bicyclic molecule , docking (animal) , receptor , combinatorial chemistry , in vitro , biochemistry , medicine , nursing
We here report on our continued studies of ligands binding to the promising drug target angiotensin II type 2 receptor (AT 2 R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT 2 R antagonist C38 , generating small but significant shifts in AT 2 R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five‐fold improved affinity to AT 2 R as compared to C38 . The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT 2 R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.