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

The synthesis and biological evaluation of a series of 1,7-cyclized indole-based human β3-adrenergic receptor (AR) agonists are described. SAR studies showed that the size of the 1,7-linker portion significantly affected subtype selectivity for the β3-AR. An unsaturated eight-membered ring analogue 26 exhibited potent agonistic activity and extremely high selectivity for human β3-AR.