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 evaluation of a novel series of 1,7-cyclized indole-based human adrenergic receptor (beta(3)-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 selecurity against the beta(1)- and beta(2)-ARs. Compound 26, an eight-membered ring analogue with a double bond on its 1.7-linker portion, was found to be a potent beta(3)-AR agonist (EC50 = 0.75 nM, IA = 90%) with extremely high selectivity for the beta(3)-AR over the beta(1)- and beta(2)-ARs. (C) 2004 Elsevier Ltd. All rights reserved.