Simultaneous Optimization of Potency, Selectivity and Physicochemical Properties for Cannabinoid CB2 Ligands

Non-selective cannabinoid ligands display a wide range of physiological effects including analgesic, antiinflammatory, anti-convulsive and immuno-suppressive activities. A separation between therapeutic effects and undesirable CNS side effects may be accomplished by increasing the selectivity for the CB2 receptor over the CB1 receptor. There is considerable interest in developing new cannabimimetic compounds possessing preferentially high affinity for the CB2 receptor as potential novel therapeutics for the treatment of inflammation and chronic pain. This review will summarize the literature on selective cannabinoid CB2 receptor agonists from 2007 to the present, with special emphasis on SAR and medicinal chemistry strategies to improve physicochemical properties, metabolic stability and oral bioavailabilty of these inherently lipophilic ligands. Incorporating physicochemical property filters early in hit identification, concurrent screening of liver microsomal stability and addressing metabolic hot-spots through structural modifications or bio-isosteric replacements during lead optimization led to a number of structurally diverse CB2 agonists with good oral bioavailability and in vivo efficacy in rodent models of pain.