RESUMEN
Novel piperidine carboxylic acid derivatives of 10H-pyrazino[2,3-b][1,4]benzothiazine were prepared and evaluated for their inhibitory activity on the upregulation of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1). Replacement of the methanesulfonyl group on the piperidine ring of previously prepared derivatives with a carboxylic acid-containing moiety resulted in a number of potent adhesion molecule inhibitors. Of these, (anti) [3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methyl-3-azabicyclo[3.3.1]non-9-yl]acetic acid 2q (ER-49890), showed the most potent oral inhibitory activities against neutrophil migration in an interleukin-1 (IL-1) induced paw inflammation model using mice, and leukocyte accumulation in a carrageenan pleurisy model in the rat, and therapeutic effect on collagen-induced arthritis in rats.
Asunto(s)
Ácidos Carboxílicos/química , Moléculas de Adhesión Celular/antagonistas & inhibidores , Piperidinas/química , Tiazinas/química , Administración Oral , Animales , Benzotiadiazinas/administración & dosificación , Benzotiadiazinas/química , Ácidos Carboxílicos/administración & dosificación , Moléculas de Adhesión Celular/fisiología , Femenino , Molécula 1 de Adhesión Intercelular/fisiología , Masculino , Piperidinas/administración & dosificación , Ratas , Ratas Endogámicas F344 , Ratas Endogámicas Lew , Tiazinas/administración & dosificaciónRESUMEN
During a search for novel, orally-active inhibitors of upregulation of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), we found a new series of 10H-pyrazino[2,3-b][1,4]benzothiazine derivatives to be potent ICAM-1 inhibitors. Of these compounds, N-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]-N',N'-dimethylsulfamide 7p showed the potent oral inhibitory activities against neutrophil migration in a murine interleukin-1 (IL-1) induced paw inflammation model. The synthesis and structure-activity relationships of these amide derivatives are described.