Structure–activity relationships of novel piperazines as antagonists for the melanocortin-4 receptor

During the investigation of antagonists for the MC4 receptor, we found that 10ab having a naphthyl group showed almost the same binding affinity for the MC4 receptor as that of the lead compound 1 with a benzoyl group. We also developed a new type of compounds, namely, bis-piperazines, and found that the bis-piperazines 10 exhibited a high affinity for the MC4 receptor. In particular, (−)-10bg exhibited the highest affinity for the MC4 receptor with an IC50 value of 8.13 nM. In this paper, we present the design, synthesis, and structure–activity relationships of the novel bis-piperazines as MC4 receptor antagonists.

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