It has been reported that bioisosteric replacement of an 1,2,4-oxadiazole ring by an 1,3,4-oxadiazole ring leads to higher polarity, reduced metabolic degradation by human liver microsomes and reduced interaction with hERG channels. In a seven to eight step synthesis 1,3,4-oxadiazles 9a-c were synthesized as bioisosteric analogs of high-affinity but rather lipophilic CB2 ligands 1a-c containing an 1,2,4-oxadiazole ring. The 1,3,4-oxadiazole derivatives 9a and 9b show 10- and 50-fold reduced CB2 affinity compared to the 1,2,4-oxadiazole derivatives 1a and 1b, respectively. However, the 1,3,4-oxadiazole 9a has high CB2 affinity (K-i = 25 nM) and high selectivity over the CB1 receptor.
