The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB Receptor Positive Allosteric Modulators.

The first generation of CB positive allosteric modulators (e.g., ZCZ011) featured a 3-nitroalkyl-2-phenyl-indole structure. Although a small number of drugs include the nitro group, it is generally not regarded as being "drug-like", and this is particularly true for aliphatic nitro groups. There are very few case studies where an appropriate bioisostere replaced a nitro group that had a direct role in binding. This may be indicative of the difficulty of replicating its binding interactions. Herein, we report the design and synthesis of ligands targeting the allosteric binding site on the CB cannabinoid receptor, in which a CF group successfully replaced the aliphatic NO. In general, the CF-bearing compounds were more potent than their NO equivalents and also showed improved in vitro metabolic stability. The CF analogue (1) with the best balance of properties was selected for further pharmacological evaluation. Pilot in vivo studies showed that (±)-1 has similar activity to (±)-ZCZ011, with both showing promising efficacy in a mouse model of neuropathic pain.