High affinity rigidified AT 2 receptor ligands with indane scaffolds

Rigidification of the isobutyl side chain of drug-like AT receptor agonists and antagonists that are structurally related to the first reported selective AT 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 , , , , , , and bind to the AT receptor with moderate ( = 54-223 nM) to high affinity ( = 2.2-7.0 nM). The enantiomer with positive optical rotation (+) exhibited the highest affinity at the receptor. The indane derivatives and are among the most potent AT receptor antagonists reported so far. As illustrated by the enantiomer pairs / and / , an alteration at the stereogenic center has a pronounced impact on the activation process of the AT receptor, and can convert agonists to antagonists and .