RESUMO
A cell-based assay for the chemokine G-protein-coupled receptor CCR4 was developed, and used to screen a small-molecule compound collection in a multiplex format. A series of bipiperidinyl carboxylic acid amides amenable to parallel chemistry were derived that were potent and selective antagonists of CCR4. One prototype compound was shown to be active in a functional model of chemotaxis, making it a useful chemical tool to explore the role of CCR4 in asthma, allergy, diabetes, and cancer.
Assuntos
Amidas/química , Amidas/farmacologia , Biperideno/química , Ácidos Carboxílicos/química , Receptores de Quimiocinas/antagonistas & inibidores , Concentração Inibidora 50 , Estrutura Molecular , Receptores CCR4 , Receptores de Quimiocinas/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
3-(2-Carboxyethyl)-4,6-dichloro-1H-indole-2-carboxylic acid (MDL-29951), an antagonist of the glycine site of the NMDA receptor, has been found to be an allosteric inhibitor of the enzyme fructose 1,6-bisphosphatase. The compound binds at the AMP regulatory site by X-ray crystallography. This represents a new approach to inhibition of fructose 1,6-bisphosphatase and serves as a lead for further drug design.