4-Cyano-5-(2-thiophenyl)-pyrazoles are high affinity CB1 receptor ligands

Abstract

Pyrazoles bearing a 5-thiophenyl and a 4-cyano group were synthesised and tested for their affinity to the cannabinoid CB₁ receptor showing in many cases single digit nanomolar K_i values and moderate to good selectivity towards the CB₂ receptor. Some of these pyrazole ligands, such as 8g, displayed relatively low lipophilicity (experimental log P < 4) and high calculated Topological Polar Surface Area (TPSA) (>90) suggesting that these compounds may behave as peripherally restricted CB₁ ligands. Furthermore, 2-fluoroethyl carboxamides 8d, 8h and 8l are interesting candidates for further development into PET tracers.