Načrtovanje, sinteza in vrednotenje zaviralcev napetostno odvisnih natrijevih in protonskih kanalčkov

The role that voltage-gated sodium and proton channels (NaV and HV1, respectively) play in neurotransmission, muscle contraction and immune response positions them in the midst of various physiological and pathological processes and makes them highly attractive pharmacological targets. However, the development of selective inhibitors is challenging due to high sequence similarity between different subtypes, which often leads to undesirable off-target effects. Additionally, suboptimal physicochemical and pharmacokinetic properties often limit their potential for in vivo efficacy. The aim of this doctoral dissertation was to overcome these limitations by developing novel inhibitors for voltage-gated sodium and proton channels with a favourable selectivity profile and improved drug-like properties. Our work specifically focused on NaV1.3 and NaV1.7 channels and their involvement in chronic neuropathic pain and on the role of hHV1 channels in tumour growth and progression. Two series of aryl sulphonamide-based hNaV1.3 inhibitors have been developed, yielding new chemical probes that offer great potential for further optimization and for elucidating the importance of the channel in the pathophysiology of pain. Ligand-based pharmacophore models based on known NaV1.7 inhibitors have been developed and validated, providing novel computational tools to accelerate NaV1.7 drug discovery. Finally, using computational methods, we have identified and subsequently optimized a new structural class of inhibitors of human HV1 channels and demonstrated their anticancer potential. Overall, we have demonstrated that our integrated approach, which combines computer-aided drug design with novel synthetic routes and pharmacological and biophysical profiling, can contribute to successfully overcome inherent challenges in voltage-gated ion channel drug discovery. The doctoral dissertation has contributed to a deeper understanding of voltage-gated ion channel pathophysiology and has facilitated the identification of novel voltage-gated ion channel inhibitors, providing a solid starting point for further research in the field of human NaV and HV1 modulators.