Optimisation of a novel series of selective CNS penetrant CB2 agonists

A series of benzimidazole CB2 receptor agonists were prepared and their properties investigated. Optimisation of the three benzimidazole substituents led to the identification of compound 23, a potent CB2 full agonist (EC50 2.7 nM) with excellent selectivity over the CB1 receptor (>3000-fold). Compound 23 demonstrated good CNS penetration in rat. Further optimisation led to the identification of compound 34 with improved selectivity over hERG and excellent CNS penetration in rat.

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