Discovery of 1,7-cyclized indoles as a new class of potent and highly selective human beta3-adrenergic receptor agonists with high cell permeability.
The synthesis and evaluation of a novel series of 1,7-cyclized indole-based human adrenergic receptor (beta3-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 beta1- and beta2-ARs. Compound 26, an eight-membered ring analogue with a double bond on its 1,7-linker portion, was found to be a potent beta3-AR agonist (EC50 = 0.75 nM, IA = 90%) with extremely high selectivity for the beta3-AR over the beta1- and beta2-ARs.
Mizuno
Kazuhiro
K
Chemistry Research Laboratories, Dainippon Pharmaceutical Co., Ltd, 33-94, Enoki, Suita 564-0053, Japan. kazuhiro-mizuno@dainippon-pharm.co.jp
Sawa
Masaaki
M
Harada
Hiroshi
H
Taoka
Ikuko
I
Yamashita
Haruhisa
H
Oue
Mayumi
M
Tsujiuchi
Hiroshi
H
Arai
Yukiyo
Y
Suzuki
Shinya
S
Furutani
Yasuji
Y
Kato
Shiro
S
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D011869:Radioligand Assay; D013329:Structure-Activity Relationship
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D007211:Indoles