Another successful example of a bioisosteric replacement of an ester functionality with an oxadiazole moiety, for improving the metabolic stability, was illustrated in the studies of piperidine-based analogs of cocaine. In an effort to increase the duration of action of the dopamine transporter 3, a 3,4-substituted piperidine-based cocaine analog 4 was synthesized in which the methyl ester group in 3 was replaced with an oxadiazole moiety (8). The affinities of 4 to the dopamine and norepinephrine transporters are very similar to 3, however, 4 showed at least a 2-fold longer duration of action when compared to ester 3.
Thiazoles and thiadiazoles have also been used as bioisosteres for ester groups (9). In the continuing search for benzodiazepine site ligands with functional selectivity for a2/a3-subtypes of human GABAa receptor-ion channels, 1-methyl-3-cyano-2-pyridone 5 emerged from screening as a low-affinity ligand with weak binding selectivity for a2 and a3 GABAa subtypes over a1. Modification of the 3-cyano group in 5 to a methyl ester and introduction of a basic pyridine to the C-6 position gave 6a which possessed higher affinities than the lead at a1, a2, and <*3 subtypes. However, the pharmacokinetic behavior of 6a in rat was poor, with rapid metabolism observed. Various heteroaryls were incorporated at the 3-position of the pyridone core of 6a as replacements for the metabolically labile methyl ester. While 6b showed negligible affinity for GABAa subtypes, isomer 6c retained some affinity, and the corresponding thiadiazole 6d showed excellent binding affinity and was a full agonist at all subtypes.
Was this article helpful?