Bioanalytical Exploitation on the Discovery of Dual H3R/QC Ligands: In Vitro Studies of Enzymatic and Pharmacokinetic Properties

• Grant number: 25/06956-6
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: October 01, 2025
• End date: March 31, 2026
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: João Paulo dos Santos Fernandes
• Grantee: Flávia Barrio Lopes
• Supervisor: Manuela Bartolini
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil
• Institution abroad: Università di Bologna, Italy
• Associated to the scholarship: 23/03485-7 - Dual H3R/QC inhibitors as alternatives for the treatment of neurodegenerative diseases, BP.DR

Abstract

The discovery and development pipeline for new drug candidates is a challenging process, especially when considering compounds designed to simultaneously act on two or more targets. In this context, two set of compounds were designed and prepared as histamine H3 receptor (H3R) antagonists and glutaminyl cyclase (QC) inhibitors, two targets for therapeutic applications in neurodegenerative diseases. Although these multitargeted compounds may represent advancements in the treatment of multifactorial diseases such as neurodegenerations, the incorporation of multiple pharmacophores into a single molecule may impair the drug-likeness and the pharmacokinetic properties. Additionally, compounds addressed to the central nervous system must cross the blood-brain barrier to effectively exert their pharmacological activity. Therefore, the early investigation of the molecular properties related to absorption, distribution, metabolism and excretion (ADME) is highly recommended. Thus, this project aims to evaluate the prepared compounds as QC inhibitors and to perform early in vitro assessment of some properties influencing pharmacokinetic behaviour, such as chemical and plasma stability, plasma protein binding and permeability, using bioanalytical methods. The assays will be carried out using well-established and validated experimental protocols, in the Biopharmaceutical and Pharmaceutical Analysis group at University of Bologna. The results will allow the potency optimization of the compounds along with desirable ADMET properties and drug-likeness and, lastly, determine structure-activity/property relationships to support the design of novel compounds. (AU)