Discovery of 1,7-cyclized indoles as a new class of potent and highly selective human β3-adrenergic receptor agonists with high cell permeability Original Research Article

The synthesis and evaluation of a novel series of 1,7-cyclized indole-based human adrenergic receptor (β3-AR) agonists are reported. The synthesis of a variety of 1,7-cyclized indole part was accomplished by the Mitsunobu reaction or a ring closing metathesis (RCM) reaction. SAR studies revealed that expansion of the ring size resulted in considerable selectivity against the β1- and β2-ARs. Compound 26, an eight-membered ring analogue with a double bond on its 1,7-linker portion, was found to be a potent β3-AR agonist (EC50 = 0.75 nM, IA = 90%) with extremely high selectivity for the β3-AR over the β1- and β2-ARs.