RESUMO
A titanium dioxide (TiO2) interconnected porous structure has been fabricated by means of atomic layer deposition of TiO2 onto a reticular sponge template. The obtained freestanding TiO2 with large surface area can be easily taken out of the water to solve a complex separation procedure. A compact and conformal nanocoating was evidenced by morphologic characterization. A phase transition, as well as production of oxygen vacancies with increasing annealing temperature, was detected by x-ray diffraction and x-ray photoelectron spectroscopy, respectively. The photocatalytic experimental results demonstrated that the powder with appropriate annealing treatment possessed excellent photocatalytic ability due to the co-action of high surface area, oxygen vacancies and the optimal crystal structure.
RESUMO
The main uric acid-lowering agents in clinical use for hyperuricemia and gout are xanthine oxidase (XO) inhibitors or urate transporter 1 (URAT1) inhibitors. While these therapies can partially control the disease, they have various limitations. The development of XO/URAT1 dual inhibitors offers the potential to enhance therapeutic potency and reduce toxicity compared with single-target inhibitors. Through scaffold hopping from the XO inhibitor febuxostat (2) and the URAT1 inhibitor probenecid (3), followed by structure-activity relationship (SAR) studies, we identified compound 27 as a potent dual inhibitor of XO and URAT1. Compound 27 demonstrated significant dual inhibition in vitro (XO IC50 = 35 nM; URAT1 IC50 = 31 nM) and exhibited favorable pharmacology and pharmacokinetic (PK) profiles in multiple species including monkeys. Furthermore, toxicity studies in rats and monkeys revealed general safety profiles, supporting that compound 27 emerges as a promising novel drug candidate with potent XO/URAT1 dual inhibition for the treatment of gout.