High affinity rigidified AT receptor ligands with indane scaffolds

Rigidification of the isobutyl side chain of drug-like AT 2 receptor agonists and antagonists that are structurally related to the first reported selective AT 2 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 AT 2 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 AT 2 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 AT 2 receptor, and can convert agonists to antagonists and vice versa . Rigidification of the isobutyl side chain of drug-like AT 2 receptor agonists and antagonists that are structurally related to the first reported selective AT 2 receptor agonist 1 (C21) delivered bioactive indane derivatives.