Small-molecule negative modulators of adrenomedullin: design, synthesis, and 3D-QSAR study.
Fiche publication
Date publication
septembre 2008
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CHOULIER Laurence
Tous les auteurs :
Roldos V, Martin-Santamaria S, Julian M, Martinez A, Choulier L, Altschuh D, de Pascual-Teresa B, Ramos A
Lien Pubmed
Résumé
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.
Référence
ChemMedChem. 2008 Sep;3(9):1345-55.