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

MedChemComm Pub Date: 2019-11-18 DOI: 10.1039/C9MD00411D

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 (EC50,CB1 = NA, EC50,CB2 = 0.067 μM) and azaindole 24 (EC50,CB1 = NA, EC50,CB2 = 0.048 μM) were found to be potent and selective CB2 receptor partial agonists, both with improved aqueous solubility.

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