Small-Molecule Negative Modulators of Adrenomedullin: Design, Synthesis, and 3D-QSAR Study

Adrenomedullin (AM) is a peptidic hormone that was isolated in 1993, the function of which is related to several diseases such as diabetes, hypertension, and cancer. Compound 1 is one of the first nonpeptidic small‐molecule negative modulators of AM, identified in a high‐throughput screen carried out at the National Cancer Institute. Herein we report the synthesis of a series of analogues of 1. The ability of the synthesized compounds to disrupt the binding between AM and its monoclonal antibody has been measured, together with surface plasmon resonance (SPR)‐based binding assays as implemented with Biacore technology. These data were used to derive a three‐dimensional quantitative structure–activity relationship (3D‐QSAR) model, with a q2 (LOO) value of 0.8240. This study has allowed us to identify relevant features for effective binding to AM: the presence of a hydrogen‐bond donor group and an aromatic ring. Evaluation of the ability of selected compounds to modify cAMP production in Rat2 cells showed that the presence of a free carboxylic acid is essential for negative AM modulation. The synthesis of a series of adrenomedullin (AM) modulators was carried out. A competitive AM monoclonal antibody assay and SPR measurements were used to evaluate the affinity of these compounds toward AM. A 3D‐QSAR study highlighted essential features for AM binding, and the derived model is a valuable tool in the design of new derivatives.