74447-33-9Relevant academic research and scientific papers
Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors
Roldán-Pe?a, Jesús M.,Romero-Real,Hicke, Javier,Maya, Inés,Franconetti, Antonio,Lagunes,Padrón, José M.,Petralla, Sabrina,Poeta, Eleonora,Naldi, Marina,Bartolini, Manuela,Monti, Barbara,Bolognesi, Maria L.,López, óscar,Fernández-Bola?os, José G.
, (2019)
Concerned by the devastating effects of Alzheimer's disease, and the lack of effective drugs, we have carried out the design of a series of tacrine-phenolic heterodimers in order to tackle the multifactorial nature of the disease. Hybridization of both pharmacophores involved the modification of the nature (imino, amino, ether) and the length of the tether, together with the type (hydroxy, methoxy, benzyloxy), number and position of the substituents on the aromatic residue. Title compounds were found to be strong and selective inhibitors of human BuChE (from low nanomolar to subnanomolar range), an enzyme that becomes crucial in the more advanced stages of the disease. The lead compound, bearing an ether-type tether, had an IC50 value of 0.52 nM against human BuChE, and a selectivity index of 323, with an 85-fold increase of activity compared to parent tacrine; key interactions were analysed using molecular modelling. Moreover, it also inhibited the self-aggregation of Aβ42, lacking neurotoxicity up to 5 μM concentration, and showed neuroprotective activity in primary rat neurons in a serum and K+ deprivation model, widely employed for reproducing neuronal injury and senescence. Moreover, low hepatoxicity effects and complete stability under physiological conditions were found for that compound. So, overall, our lead compound can be considered as a promising multitarget-directed ligand against Alzheimer's disease, and a good candidate for developing new drugs.
Non-urea functionality as the primary pharmacophore in soluble epoxide hydrolase inhibitors
Anandan, Sampath-Kumar,Do, Zung N.,Webb, Heather K.,Patel, Dinesh V.,Gless, Richard D.
body text, p. 1066 - 1070 (2009/09/04)
Inhibition of soluble epoxide hydrolase has been proposed as a promising new pharmaceutical target for diseases involving hypertension and vascular inflammation. The most potent sEH inhibitors reported to date contain a urea or amide moiety as the central or 'primary' pharmacophore. We evaluated replacing the urea pharmacophore with other functional groups such as thiourea, sulfonamide, sulfonylurea, aminomethylene amide, hydroxyamide, and ketoamide to identify novel and potent inhibitors. The hydroxyamide moiety was identified as a novel pharmacophore affording potency comparable to urea.
