New amidine-benzenesulfonamides as iNOS inhibitors for the therapy of the triple negative breast cancer.

Triple negative breast cancer (TNBC) is a specific breast cancer subtype, and poor prognosis is associated to this tumour when it is in the metastatic form. The overexpression of the inducible Nitric Oxide Synthase (iNOS) is considered a predictor of poor outcome in TNBC patients, and this enzyme is reported as a valuable molecular target to compromise TNBC progression. In this work, new amidines containing a benzenesulfonamide group were designed and synthesized as selective iNOS inhibitors.

Antiglioma Activity of Aryl and Amido-Aryl Acetamidine Derivatives Targeting iNOS: Synthesis and Biological Evaluation.

Nitric oxide is an important inflammation mediator with a recognized role in the development of different cancers. Gliomas are primary tumors of the central nervous system with poor prognosis, and the expression of the inducible nitric oxide synthase correlates with the degree of malignancy, changes in vascular reactivity, and neo-angiogenesis. Therefore, targeting the nitric oxide biosynthesis appears as a potential strategy to impair glioma progression.

Druggability profile of stilbene-derived PPAR agonists: determination of physicochemical properties and PAMPA study.

PPAR agonists represent a new therapeutic opportunity for the prevention and treatment of neurodegenerative disorders, but their pharmacological success depends on favourable pharmacokinetic properties and capability to cross the BBB. In this study, we assayed some PPAR agonists previously synthesized by us for their physicochemical properties, with particular references to lipophilicity, solubility and permeability profiles, using the PAMPA. Although tested compounds showed high lipophilicity and low aqueous solubility, the results revealed a good overall druggability profile, encouraging further studies in the field of neurodegenerative diseases.

Multitarget PPARγ agonists as innovative modulators of the metabolic syndrome.

A multitarget pharmacologic approach could be advantageous for the therapy of metabolic multiple diseases, such as the metabolic syndrome, which is characterized by metabolic abnormalities associated with diabetes, obesity, hypertension, and increased cardiovascular risk. PPAR receptors play a critical role in metabolic disorders, affecting glucose and lipid metabolism. Drugs simultaneously targeting PPAR and other validated metabolic targets, represent a promising multitarget approach to combine antihyperglycemic, antihyperlipidemic, and antihypertensive effects.

The Selective Acetamidine-Based iNOS Inhibitor CM544 Reduces Glioma Cell Proliferation by Enhancing PARP-1 Cleavage In Vitro.

Gliomas are the most aggressive adult primary brain tumors. Expression of inducible Nitric Oxide Synthase has been reported as a hallmark of chemoresistance in gliomas and several studies have reported that inhibition of inducible Nitric Oxide Synthase could be related to a decreased proliferation of glioma cells. The present work was to analyze the molecular effects of the acetamidine derivative compound 39 (formally CM544, -(3-{[(1-iminioethyl)amino]methyl}benzyl) prolinamide dihydrochloride), a newly synthetized iNOS inhibitor, in a C6 rat glioma cell model.

Discovery of new FXR agonists based on 6-ECDCA binding properties by virtual screening and molecular docking.

FXR is a member of the nuclear receptor superfamily, which regulates the expression of various genes involved in bile acid, lipid and glucose metabolism. Targeting FXR with small molecules has been exploited to treat lipid-related disorders and diseases such as cholestasis, gallstones and hepatic disorders. In this work, we expand the existing pool of known FXR agonists using a fast hit-to-lead structure-based pharmacophore and docking screening protocol.

Discovery of N-{3-[(ethanimidoylamino)methyl]benzyl}-l-prolinamide dihydrochloride: A new potent and selective inhibitor of the inducible nitric oxide synthase as a promising agent for the therapy of malignant glioma.

In mammalian cells, aberrant iNOS induction may have detrimental consequences, and seems to be involved in the proliferation and progression of different tumors, such as malignant gliomas. Therefore, selective inhibition of iNOS could represent a feasible therapeutic strategy to treat these conditions. In this context, we have previously disclosed new acetamidines able to inhibit iNOS with a very high selectivity profile over eNOS or nNOS.