title: Small-molecule negative modulators of adrenomedullin: design, synthesis, and 3D-QSAR study.
abstract: 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.
authors.affiliation: Departamento de Química, Facultad de Farmacia, Universidad San Pablo CEU, Boadilla del Monte, 28668 Madrid, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Roldós
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Martín-Santamaría
authors.forename: Miguel
authors.initials: M
authors.lastname: Julián
authors.forename: Alfredo
authors.initials: A
authors.lastname: Martínez
authors.forename: Laurence
authors.initials: L
authors.lastname: Choulier
authors.forename: Danièle
authors.initials: D
authors.lastname: Altschuh
authors.forename: Beatriz
authors.initials: B
authors.lastname: de Pascual-Teresa
authors.forename: Ana
authors.initials: A
authors.lastname: Ramos