RESUMEN
To search for TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the P1 and P2' residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1-P2' linkers. With an N-methylamide at P3', the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-alpha release from LPS-stimulated human whole blood. Further elaboration in the P3'-P4' area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC(50) values of
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Ácidos Hidroxámicos/síntesis química , Lactamas/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Proteínas ADAM , Proteína ADAM17 , Administración Oral , Animales , Disponibilidad Biológica , Carbamatos/síntesis química , Carbamatos/química , Carbamatos/farmacocinética , Carbamatos/farmacología , Perros , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacocinética , Ácidos Hidroxámicos/farmacología , Técnicas In Vitro , Lactamas/química , Lactamas/farmacocinética , Lactamas/farmacología , Masculino , Ratones , Estereoisomerismo , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/análisisRESUMEN
Several macrocyclic, hydroxamate derivatives were synthesized and evaluated as inhibitors of matrix metalloproteinases (MMPs) and tumour necrosis factor-alpha (TNF-alpha) production. These macrocycles are anti-succinate based inhibitors linked from P1 to P2'. A variety of functionality was installed at the P1-P2' linkage, which gave inhibitors that displayed excellent MMP inhibition and good TNF-alpha suppression.
