Discovery of 1,3-disubstituted pyrazole peripheral cannabinoid receptor partial agonists

Partial agonists of peripheral cannabinoid receptors (CBRs) have potential therapeutic applications in several medical conditions. However, (-)-trans-Delta(9-)tetrahydrocannabinol (THC), the principal active component of marijuana, which is a partial agonist of CB1 and CB2 penetrates the central nervous system (CNS) and produces adverse effects. Peripherally restricted partial agonists of CBRs, particularly of CB1, can be used to treat illnesses safely and effectively with a better therapeutic index. Here, we report on our efforts to synthesize pyrazole partial CBR agonists with peripheral selectivity, resulting in lead compound 40. This compound is a potent partial agonist of CB1 with similar to 5-fold higher plasma biodistribution over brain and represents an early lead for optimization.

Automated summary

Partial agonists of peripheral cannabinoid receptors (CBRs) have potential therapeutic applications in several medical conditions. However, the principal active component of marijuana, THC, penetrates the central nervous system and produces adverse effects. Peripherally restricted partial agonists of CBRs, particularly of CB1, can be used to treat illnesses safely and effectively with a better therapeutic index. The lead compound 40, a pyrazole partial CBR agonist with peripheral selectivity, shows promising potential for optimization with its high plasma biodistribution over the brain.