Small-molecule negative modulators of adrenomedullin: design, synthesis, and 3D-QSAR study.
ChemMedChem
; 3(9): 1345-55, 2008 Sep.
Article
em En
| MEDLINE
| ID: mdl-18759242
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Ligação Competitiva
/
Relação Quantitativa Estrutura-Atividade
/
Adrenomedulina
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article