Discovery of a 3,4,5-trisubstituted-1,2,4-triazole agonist with high affinity and selectivity at the somatostatin subtype-4 (sst4) receptor

Abstract

A series of compounds containing a 1,2,4-triazole moiety were synthesized, targeting the somatostatin receptor subtype-4 (sst₄). Compounds were developed in which the Phe⁶/Phe⁷/Phe¹¹, Trp⁸, and Lys⁹ 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 sst₄. 1,2,4-Triazoles containing an (indol-3-yl)methyl substituent at position-5 lacked affinity at sst₄. 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 44) imparted high affinity and selectivity at sst₄ (sst_2A = >10 000 nM; sst₄ = 19 nM), acting as an agonist (EC₅₀ = 6.8 nM). Docking 44 into a model-built structure of sst₄ pointed to differences in its binding versus 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 44 among the top-ranked poses. In summary, compound 44 represents a novel and promising lead structure towards the development of a clinically viable sst₄ agonist for the treatment of conditions ranging from Alzheimer's disease to chronic pain.