From a Designer Drug to the Discovery of Selective Cannabinoid Type 2 Receptor Agonists with Favorable Pharmacokinetic Profiles for the Treatment of Systemic Sclerosis

Synthetic
cannabinoids, as exemplified by SDB-001 (1), bind to
both CB1 and CB2 receptors and exert cannabimimetic effects
similar to (−)-trans-Δ9-tetrahydrocannabinol,
the main psychoactive component present in the cannabis plant. As
CB1 receptor ligands were found to have severe adverse psychiatric
effects, increased attention was turned to exploiting the potential
therapeutic value of the CB2 receptor. In our efforts to discover
novel and selective CB2 receptor agonists, 1 was selected
as a starting point for hit molecule identification and a class of
1H-pyrazole-3-carboxamide derivatives were thus designed,
synthesized, and biologically evaluated. Systematic structure–activity
relationship investigations resulted in the identification of the
most promising compound 66 as a selective CB2 receptor
agonist with favorable pharmacokinetic profiles. Especially, 66 treatment significantly attenuated dermal inflammation
and fibrosis in a bleomycin-induced mouse model of systemic sclerosis,
supporting that CB2 receptor agonists might serve as potential therapeutics
for treating systemic sclerosis.