Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, TRANSMEMBRANE CONDUCTANCE REGULATOR, CORRECTORS, DISCOVERY, COMPLEXITY, INHIBITORS, EFFICIENCY, DEFECTS, Animals, Antiviral Agents, Cell Survival, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Drug Delivery Systems, Humans, Male, Membranes, Artificial, Mice, Mice, Inbred C57BL, Microsomes, Liver, Permeability, Protein Binding, Serum Albumin, Human, Toxicity Tests, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

Cystic fibrosis (CF) is a multiorgan disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR). In addition to respiratory impairment due to mucus accumulation, viruses and bacteria trigger acute pulmonary exacerbations, accelerating disease progression and mortality rate. Treatment complexity increases with patients' age, and simplifying the therapeutic regimen represents one of the key priorities in CF. We have recently reported the discovery of multitarget compounds able to "kill two birds with one stone" by targeting F508del-CFTR and PI4KIIIβ and thus acting simultaneously as CFTR correctors and broad-spectrum enterovirus (EV) inhibitors. Starting from these preliminary results, we report herein a hit-to-lead optimization and multidimensional structure-activity relationship (SAR) study that led to compound 23a. This compound showed good antiviral and F508del-CFTR correction potency, additivity/synergy with lumacaftor, and a promising in vitro absorption, distribution, metabolism, and excretion (ADME) profile. It was well tolerated in vivo with no sign of acute toxicity and histological alterations in key biodistribution organs.