Estrategias en el tratamiento de la enfermedad renal crónicanuevos moduladores de PTP 1B e ILK

Abstract

The research group joined in 2011 to one of the NETWORKS (RETICS) promoted by the Spanish Instituto de Salud Carlos III, REDinREN. The role of our research group in this network is to contribute to the search for new compounds that could be of interest for new and relevant targets involved in the development and progression of Chronic Kidney Disease (CKD). The present thesis has been focused on the application of medicinal and biological chemistry approaches for the treatment of CKD. This in one of the most important contributor to morbidity and mortality of non-transmissible diseases. This term collect several disorders affecting kidney structure and function, generally glomerular filtration rate 60 mL/min/1.73 m2 or albuminuria ³30 mg per 24 hours) for more than 3 months. In the late stages, it produces the kidney failure or end-stage renal disease, which requires renal replacement therapy. During 2017, the global prevalence of CKD was 9.1% which is about 700 million cases, and since 1990, its prevalence has increased by 29.3%, especially in elderly population of developed countries. Furthermore, it remains among the growing causes of mortality which made CKD the 13th leading cause of death in 2013.5 Moreover, it supposes a big burden for current health care systems. As example, those patients treated through renal replacement therapy consume more than the 5% of health care budgets. Nowadays the origin of CKD it is unknow, but the main causes are: diabetes mellitus type II (44%), followed by hypertension (28%) and other non-related and idiopatic causes. Despite of this scenario, there is no pharmacological treatment for this disease. Only canaglifozine (an SGLT2 inhibitor) of Jannsen laboratories has entered in Phase II Clinical Trials to reduce the risk of end-stage kidney disease in an attempt of drug-repurposing. Then, in this context this thesis has followed different approaches to get new outcomes for the treatment or the study of this disease. Protein Tyrosine Phosphatase 1B (PTP1B) has been claimed as a promising target for diabetes mellitus type II, and its inhibition may be the best approach for the treatment of CKD. Despite the wide variety of PTP1B inhibitors described in the literature, just only allosteric inhibitors have reached clinical trials. In our research group, the scaffold pyrrolo[1,2-a]quinoxaline was identified as inhibitor of PTP1B in a collaboration with Servier Laboratories. In this context, during the first chapter, different positions of this scaffold were explored in order to improve the potency and/or physicochemical properties. Then, in vitro activity was determined for new and previously prepared compounds in order to identify the most interesting ones. Moreover, computational methods have been employed to explain the behaviour and/or activity observed for the different series of compounds. During the pre-doctoral research stay at the University of Bristol, computational approaches, mainly molecular dynamics and Water Swap free energy methods, were also tested on selected compounds with the aim of shedding some light onto the experimentally observed results. Regarding the second chapter of this work, the novel target ILK was explored. This is a protein which in recent years has been tightly related to chronic kidney disease and kidney function in several studies. ILK regulates processes such as renal fibrosis, kidney development or immune response in kidney. In the last decade this enzyme was proposed as a new cancer target, however its role in kidney disease remains unclear. An approach non-explored before was carried out to design new molecules based on its protein-protein interaction with -parvin. Following an in silico proposal, different series of peptides were synthesized and tested in different experiments in order to obtain new tools for the study of this protein.