2015, Publicación

Rodríguez-Sanz et al. Eur. J. Med. Chem.. 2015;:83-92. Synthesis and biological evaluation of pyridazino[1′,6′:1,2]pyrido[3,4-b]indolinium and pyridazino[1,6-a]benzimidazolium salts as anti-inflammatory agents.

Publicaciones > Rodríguez-Sanz et al

Eur. J. Med. Chem. 2015 Mar; :83-92.

Synthesis and biological evaluation of pyridazino[1′,6′:1,2]pyrido[3,4-b]indolinium and pyridazino[1,6-a]benzimidazolium salts as anti-inflammatory agents.

Aranzazu Rodríguez-Sanz1, Patricia Sánchez-Alonso2, Teresa Bellón1, Ramón Alajarín2, Virginia Martínez-Cabeza1, Rafael Selgas3, Juan J. Vaquero2, Julio Álvarez-Builla2

1. Instituto de Salud Hospital Universitario La Paz – IdiPAZ, Madrid, Spain.  2. Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Madrid, Spain.  3. Hospital Universitario La Paz, Servicio de Nefrología, IdiPAZ, IRSIN, Madrid, Spain.

Abstract

Condensed polycyclic heteroaromatic cations bearing a bridgehead nitrogen with pyridazino[1′,6′:1,2]pyrido[3,4-b]indolinium and pyridazino[1,6-a]benzimidazolium structures were assayed as inhibitors of LPS-induced TNF-α production by THP-1 cells. The hit compound 1e, which had the best IC50 value (4.49 μM) and low toxicity, was further assayed on human PMBCs (IC50 3.91 μM) and monocytes (IC50 1.82 μM). This compound also inhibited TNF-α production following poly I:C stimulation of human monocytes and monocyte-derived dendritic cells; in the latter case, inhibition of IL-12 production was also observed. Compound 1e was also able to inhibit TNF-α expression at the transcriptional level and proved to be effective in vivo. Compound 1e is an interesting potential therapeutic agent in IMIDs.