High affinity rigidified AT₂ receptor ligands with indane scaffolds

Rigidification of the isobutyl side chain of drug-like AT₂ receptor agonists and antagonists that are structurally related to the first reported selective AT₂ receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >99%. The enantiomers 7a, 7b, 8a, 8b, 9a, 9b, 10a and 10b bind to the AT₂ receptor with moderate (K _i = 54-223 nM) to high affinity (K _i = 2.2-7.0 nM). The enantiomer with positive optical rotation (+) exhibited the highest affinity at the receptor. The indane derivatives 7b and 10a are among the most potent AT₂ receptor antagonists reported so far. As illustrated by the enantiomer pairs 7a/b and 10a/b, an alteration at the stereogenic center has a pronounced impact on the activation process of the AT₂ receptor, and can convert agonists to antagonists and vice versa.