Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists

A novel CBI receptor agonist lead series was identified using a high-throughput screening approach. The initial screen afforded a single confirmed hit with poor water solubility. Structural variations were explored with the aim of introducing water solubility and improving potency. This led to the discovery of Org 28611, a potent, water soluble CBI receptor agonist, which was selected for clinical evaluation as a potential intravenous analgesic agent.