Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: Design, synthesis, structure-activity relationships, physicochemical properties and biological activity

作者：Blaazer Antoni R^*; Lange Jos H M; van der Neut Martina A W; Mulder Arie; den Boon Femke S; Werkman Taco R; Kruse Chris G; Wadman Wytse J

来源：European Journal of Medicinal Chemistry, 2011, 46(10): 5086-5098.

DOI：10.1016/j.ejmech.2011.08.021

• Azaindole
• Cannabinoid receptor agonist
• Indole
• Physicochemical properties
• Pyrrolopyridine
• Structure-activity relationships

The discovery, synthesis and structure-activity relationship (SAR) of a novel series of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor ligands are reported. Based on the aminoalkylindole class of cannabinoid receptor agonists, a biphenyl moiety was introduced as novel lipophilic indole 3-acyl substituent in 11-16. Furthermore, the 3-carbonyl tether was replaced with a carboxamide linker in 17-20 and the azaindole (pyrrolopyridine) nucleus was designed as indole bioisostere with improved physicochemical properties in 21-25. Through these SAR efforts, several high affinity CB1/CB2 dual cannabinoid receptor ligands were identified. Indole-3-carboxamide 17 displayed single-digit nanomolar affinity and similar to 80 fold selectivity for CB1 over the CB2 receptor. The azaindoles displayed substantially improved physicochemical properties (lipophilicity: aqueous solubility). Azaindole 21 elicited potent cannabinoid activity. Cannabinoid receptor agonists 17 and 21 potently modulated excitatory synaptic transmission in an acute rat brain slice model of cannabinoid receptor-modulated neurotransmission.

• 出版日期2011-10