Discovery of a 3,4,5-trisubstituted-1,2,4-triazole agonist with high affinity and selectivity at the somatostatin subtype-4 (sst) receptor.

A series of compounds containing a 1,2,4-triazole moiety were synthesized, targeting the somatostatin receptor subtype-4 (sst). Compounds were developed in which the Phe/Phe/Phe, Trp, and Lys mimetic groups were interchanged at positions 3, 4, and 5 of the 1,2,4-triazole ring. The 1,2,4-triazoles containing an 2-(imidazol-4-yl)ethyl substituent at position-3 demonstrated moderate binding affinity at sst. 1,2,4-Triazoles containing an (indol-3-yl)methyl substituent at position-5 lacked affinity at sst. The 1,2,4-triazoles containing an aminopropyl group at position-4 showed enhanced binding affinity compared to the 3-position. One compound with an 3-(imidazol-4-yl)propyl group at position-4 (compound ) imparted high affinity and selectivity at sst (sst = >10 000 nM; sst = 19 nM), acting as an agonist (EC = 6.8 nM). Docking into a model-built structure of sst pointed to differences in its binding the other low-affinity compounds and was also in line with one of the two previously reported binding modes. A virtual screening (VS) experiment, employing two separate docking algorithms, was able to score among the top-ranked poses. In summary, compound represents a novel and promising lead structure towards the development of a clinically viable sst agonist for the treatment of conditions ranging from Alzheimer's disease to chronic pain.