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Incliva researchers synthesize and evaluate the efficacy of a new drug to prevent pathologies


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Incliva researchers synthesize and evaluate the efficacy of a new drug to prevent pathologies


Three research groups from the Incliva Health Research Institute, of the Hospital Clínico de Valencia, have come together to develop and study the pharmacological activity of a new drug that, in addition to improving plasma glucose and triglyceride levels, has anti-inflammatory activity with interest for the prevention of the development of cardiovascular pathologies in patients with metabolic disorders.

The Inflammation Research Group --coordinated by Dr. María Jesús Sanz--, the Research Group in Medicinal Chemistry for Drug Development --coordinated by doctors Nuria Cabedo and Diego Cortes--, and the Research Group in Nuclear Receptors in Cardiometabolic Pathologies --coordinated by Dr. Laura Piqueras--, have been working together to synthesize a compound (BP-2), with pan-PPAR activity, and to evaluate its effect on the metabolic profile, both in vitro and in vivo, as well as its possible anti-inflammatory activity.

In addition to those mentioned, the researchers Patrice Marques, Carlos Villarroel-Vicente, Aida Collado, Ainhoa ​​García and Laura Vila, from Incliva, as well as members of the group led by Dr. Bart Staels, from the Institut Pasteur de Lille (France), and Dr. Ricardo Enriz, from the National University of San Luis (Argentina).

PPARs are receptors activated by peroxisome proliferators, involved in various metabolic pathways. Pan-PPARs are agonists (the name given to molecules that activate a therapeutic target and exert a pharmacological effect) of the three subtypes of this type of receptor: PPARa, PPAR*/d and PPAR?.

Currently, drugs that activate a single subtype of PPARs (selective agonists) are widely used in clinical practice to treat different metabolic complications.

However, the limited effect of PPARα selective agonists on glucose metabolism and the adverse effects associated with PPARα selective activators have raised interest in the development of novel dual (PPARα/?) and pan-PPAR agonists ( PPARa/d/?) to treat metabolic disorders such as Metabolic Syndrome.

The Metabolic Syndrome is a multifactorial pathology, closely associated with the development of other diseases, such as type 2 diabetes, cardiovascular diseases and cancer.

There is evidence that the Metabolic Syndrome is linked to low-grade systemic inflammation, which seems to be the main trigger of the cardiovascular complications associated with this metabolic disorder.

The polypharmacy of patients who suffer from it is usually frequent, so the development of a drug that regulates the metabolic profile with inflammatory activity "could substantially reduce the number of drugs consumed and adherence problems, in addition to reducing the incidence of reactions secondary diseases and prevent the development of cardiovascular pathologies", they have pointed out from the Incliva.

In this multicenter study, different in vitro techniques were used to investigate the effect of BP-2 on leukocyte-endothelium interactions, processes that occur when leukocytes, or white blood cells, move through the endothelial layer that lines blood vessels. looking for sites of inflammation or infection.

These interactions are an essential part of the immune system and play an important role in protecting the body against infections and diseases and constitute a crucial stage in the development of cardiovascular pathologies.

In addition, an animal model of Metabolic Syndrome was used to study the impact of BP-2 on metabolic disorders and inflammation.

Specifically, some mice were treated with this pan-PPAR agonist at 10 and 30 mg/kg/day orally for 15 days and the results were compared with a control group.

At the in vitro level, the results indicated that BP-2 reduced leukocyte-endothelium interactions through decreased expression of relevant cell adhesion molecules and chemokines.

In vivo, BP-2 significantly reduced circulating glucose and triglyceride levels, as well as levels of the proinflammatory cytokine TNFa in this animal model.

Furthermore, BP-2 suppressed immune cell infiltration into the liver and adipose tissue of these animals and modulated gene expression toward an anti-inflammatory profile.

Thus, the present investigation allowed us to conclude that BP-2 is positioned as a potential pan-PPAR candidate to normalize plasma glucose (glycemia) and triglyceride (triglyceridemia) levels, as well as to minimize systemic inflammation in metabolic disorders, preventing, probably the development of cardiovascular complications.

The results obtained throughout the development of this project have been presented at various national and international scientific conferences and have recently been published in the journal Pharmacological Research.

In addition, the synthesis of the pan-PPAR BP-2 agonist has generated a patent in which Incliva, together with the University of Valencia, appear as holders.

This work has been financed by the Ministry of Science and Innovation of Spain; the Carlos III Health Institute (ISCIII) and the European Regional Development Fund (FEDER); the Valencian Generalitat; the Agence Nationale pour la Recherche (France) and the European Research Council.