Dianas implicadas en la enfermedad renalsíntesis y evaluación de nuevos inhibidores de PTP-1B y FABP

Resumen

Diabetes mellitus is a chronic multifactorial metabolic disease caused by insulin deficiency or insuline resistance. Diabetes is often associated with cardiovascular risk factors, and may lead to severe secondary complications, including atherosclerosis, microangiopathy, renal dysfunction and failure, cardiac abnormalities, diabetic retinopathy and ocular disorders. Insuline resistance is a major pathophysiological factor in the development of type 2 diabetes and it is associated not only with hyperinsulinemia and hyperglycemia but also with other disorders such as atherosclerosis, hypertension and abnormal lipid profile, which are known collectively referred to as Metabolic Syndrome or Insuline Resistance Associated Disorders. This work focused on the synthesis and biological activity of new compounds designed as inhibitors of Protein Tyrosine Phosphatase 1B (PTP-1B) and Fatty Acid Binding Proteins (FABPs). These two therapeutic targets, are involved in diseases such as obesity, diabetes or atherosclerosis. Series of dihydropyrrolo-quinoxalines, pyrrolo-quinoxalinium salts and pyridazino-pyrrolo-quinoxalinium salts were obtained and evaluated for in vitro inhibition of PTP1B. Structure-activity relationships (SAR) where established. Dihydropyrrolo-quinoxaline serie showed inhibition in micromolar range. Molecular modeling by docking studies of pyridazino-pyrrolo-quinoxalinium salts showed binding at the allosteric site. Series of [alfa]-, [beta]-, [gamma]- and [delta]-carboline alkanoic acids and carboxyalkyl [alfa]-, [beta]-, [gamma]- and [delta]--carbolinium salts were synthesized and evaluated for in vitro inhibition of TNF-[alfa] synthesis in THP-1 cells. [alfa]- and [gamma]-carbolinium derivatives were the most active and the carboxy moiety was further modified. Best inhibition results were obtained for N-(15-carboxypentadecyl)-[gamma]-carbolinium. Inhibition of FABP4 binding was also evaluated for the [alfa]-carbolinium serie resulting in inhibitions in the same magnitude order than the reference. A methodology to synthesize dihydroderivatives of [beta]- and [gamma]-carbolines from the corresponding indol-2- and indol-3-ylmethyl TosMIC derivatives was explored. 2,3-dihydroindenimines and indole-2- and indole-3-carbonitrile derivatives were obtained through a isocyanide-nitrile long distance rearrangement.