Combinatorial synthesis and biological evaluation of peptide-binding GPCR-targeted library

As an effective strategy of the drug discovery for peptide-binding GPCRs based on the natural ligands, beta-turn peptidomimetic compound library with benzodiazepine skeleton was constructed using solid and solution phase parallel synthesis with four different scaffolds containing Phe, Lys, Ser and Glu, respectively. The usefulness of 162 library compounds was evaluated by the cell based screening at melanocortin 4 receptor in CHO-k1 cells, to find hit compounds showing agonistic effect at the receptor. The screening of library afforded three hit compounds including the most effective analog, (S)-3-benzyl-7-(4-fluorobenzyloxy)-4-(4-methoxyphenethyl)-4,5-dihydro-1H-benzo[e][1,4]diazepin-2(3H)-one, 13aiE, of which EC50 was determined as 13 μM.

Graphical abstractA series of benzodiazepine compound library designed as a beta-turn peptidomimetics have been synthesized and evaluated with a cell based screening at melanocortin 4 receptor, resulting in the generation of hit compounds having agonistic activities.Figure optionsDownload full-size imageDownload as PowerPoint slide