Introducing nitrogen atoms to amidoalkylindoles: potent and selective cannabinoid type 2 receptor agonists with improved aqueous solubility

Yue-Yang Ji; Zhi-Long Wang; Fang-Ning Pei; Jun-Jie Shi; Jiao-Jiao Li; Hendra Gunosewoyo; Fan Yang; Jie Tang; Xin Xie; Li-Fang Yu

doi:10.1039/C9MD00411D

Introducing nitrogen atoms to amidoalkylindoles: potent and selective cannabinoid type 2 receptor agonists with improved aqueous solubility†

Yue-Yang Ji,‡^a Zhi-Long Wang,‡^b Fang-Ning Pei,^a Jun-Jie Shi,^a Jiao-Jiao Li,^a Hendra Gunosewoyo,

^c Fan Yang,

^a Jie Tang,^d Xin Xie*^b and Li-Fang Yu

*^a

Author affiliations

* Corresponding authors

^a Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
E-mail: lfyu@sat.ecnu.edu.cn

^b CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China
E-mail: xxie@simm.ac.cn

^c School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia

^d Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China

Abstract

Previously we identified a series of amidoalkylindoles as potent and selective CB₂ partial agonists. In the present study, we report our continuous effort to improve the aqueous solubility by introducing N atoms to the amidoalkylindole framework. Synthesis, characterization, and pharmacology evaluations were described. Bioisosteric replacements of the indole nucleus with an indazole, azaindole and benzimidazole were explored. Benzimidazole 43 (EC_50,CB₁ = NA, EC_50,CB₂ = 0.067 μM) and azaindole 24 (EC_50,CB₁ = NA, EC_50,CB₂ = 0.048 μM) were found to be potent and selective CB₂ receptor partial agonists, both with improved aqueous solubility.

MedChemComm

Introducing nitrogen atoms to amidoalkylindoles: potent and selective cannabinoid type 2 receptor agonists with improved aqueous solubility†

Abstract

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Introducing nitrogen atoms to amidoalkylindoles: potent and selective cannabinoid type 2 receptor agonists with improved aqueous solubility

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