Dual H3R/QC inhibitors as alternatives for the treatment of neurodegenerative diseases

• Grant number: 23/03485-7
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: August 01, 2023
• End date: July 31, 2027
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: João Paulo dos Santos Fernandes
• Grantee: Flávia Barrio Lopes
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil
• Associated scholarship(s): 25/06956-6 - Bioanalytical Exploitation on the Discovery of Dual H3R/QC Ligands: In Vitro Studies of Enzymatic and Pharmacokinetic Properties, BE.EP.DR

Abstract

The design of molecules able to interact with more than one target simultaneously has been explored as a strategy in the treatment of complex diseases, such as neurodegenerative diseases, in which different pathophysiological mechanisms are involved. Many neurodegenerative diseases, such as Alzheimer's disease, dementia with Lewy bodies, among others, are characterized by the accumulation of defective or misfolded proteins that are more prone to the formation of neurotoxic aggregates. Regarding this, the neuronal death present in these clinical conditions often leads to the loss of functions related to learning and memory. In this context, the involvement of glutaminyl cyclase with the formation of peptides more prone to aggregation and to neurotoxic action has gained increasing relevance. Added to that, the recognized involvement of histamine H3 receptors with cognitive processes highlights how the modulation of both targets can represent a significant advance in the treatment of proteinopathies associated to cognitive impairment. Thus, this project aims to synthesize and evaluate the potential of compounds as histamine H3 receptor antagonists and glutaminyl cyclase inhibitors, designed through the combination of structural requirements for the interaction with these selected targets. The evaluation of the relative selectivity against other histamine receptors will also be carried out. The compounds will be prepared using synthetic methodologies well established in the group, which generally lead to good yields. In the end, it is expected to identify agents with activity in the selected targets, which can bring information about structure activity relationships that allow planning new superior compounds. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

LOPES, FLAVIA BARRIO; FERNANDES, JOAO PAULO S.; ULIASSI, ELISA. Tackling Neuroinflammation in Cognitive Disorders with Single-Targeted and Multi-Targeted Histamine H₃ Receptor Modulators. CURRENT TOPICS IN MEDICINAL CHEMISTRY, v. 24, n. 28, p. 10-pg., 2024-08-23. (23/03485-7, 19/24028-8)