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Small‐Molecule Negative Modulators of Adrenomedullin: Design, Synthesis, and 3D‐QSAR Study
Author(s) -
Roldós Virginia,
MartínSantamaría Sonsoles,
Julián Miguel,
Martínez Alfredo,
Choulier Laurence,
Altschuh Danièle,
de PascualTeresa Beatriz,
Ramos Ana
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800066
Subject(s) - adrenomedullin , quantitative structure–activity relationship , chemistry , loo , surface plasmon resonance , high throughput screening , stereochemistry , ring (chemistry) , molecule , combinatorial chemistry , biochemistry , receptor , nanotechnology , nanoparticle , organic chemistry , materials science
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 q 2 (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.