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Bioorg Med Chem. 2005 Feb 1;13(3):855-68.

Discovery of 1,7-cyclized indoles as a new class of potent and highly selective human beta3-adrenergic receptor agonists with high cell permeability.

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1
Chemistry Research Laboratories, Dainippon Pharmaceutical Co., Ltd, 33-94, Enoki, Suita 564-0053, Japan. kazuhiro-mizuno@dainippon-pharm.co.jp

Abstract

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.

PMID:
15653351
DOI:
10.1016/j.bmc.2004.10.032
[Indexed for MEDLINE]
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