142643-29-6Relevant articles and documents
Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents
Knez, Damijan,Brus, Boris,Coquelle, Nicolas,Sosi?, Izidor,?ink, Roman,Brazzolotto, Xavier,Mravljak, Janez,Colletier, Jacques-Philippe,Gobec, Stanislav
, p. 4442 - 4452 (2015)
Tremendous efforts have been dedicated to the development of effective therapeutics against Alzheimer's disease, which represents the most common debilitating neurodegenerative disease. Multifunctional agents are molecules designed to have simultaneous effects on different pathological processes. Such compounds represent an emerging strategy for the development of effective treatments against Alzheimer's disease. Here, we report on the synthesis and biological evaluation of a series of nitroxoline-based analogs that were designed by merging the scaffold of 8-hydroxyquinoline with that of a known selective butyrylcholinesterase inhibitor that has promising anti-Alzheimer properties. Most strikingly, compound 8g inhibits self-induced aggregation of the amyloid beta peptide (Aβ1-42), inhibits with sub-micromolar potency butyrylcholinesterase (IC50 = 215 nM), and also selectively complexes Cu2+. Our study thus designates this compound as a promising multifunctional agent for therapeutic treatment of Alzheimer's disease. The crystal structure of human butyrylcholinesterase in complex with compound 8g is also solved, which suggests ways to further optimize compounds featuring the 8-hydroxyquinoline scaffold.
The Magic of Crystal Structure-Based Inhibitor Optimization: Development of a Butyrylcholinesterase Inhibitor with Picomolar Affinity and in Vivo Activity
Ko?ak, Urban,Brus, Boris,Knez, Damijan,?akelj, Simon,Trontelj, Jurij,Pi?lar, Anja,?ink, Roman,Juki?, Marko,?ivin, Marko,Podkowa, Adrian,Nachon, Florian,Brazzolotto, Xavier,Stojan, Jure,Kos, Janko,Coquelle, Nicolas,Sa?at, Kinga,Colletier, Jacques-Philippe,Gobec, Stanislav
, p. 119 - 139 (2018/01/01)
The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease, thus classifying BChE as a promising drug target in advanced Alzheimer's disease. We used structure-based drug discovery approaches to develop potent, selective, and reversible human BChE inhibitors. The most potent, compound 3, had a picomolar inhibition constant versus BChE due to strong cation-π interactions, as revealed by the solved crystal structure of its complex with human BChE. Additionally, compound 3 inhibits BChE ex vivo and is noncytotoxic. In vitro pharmacokinetic experiments show that compound 3 is highly protein bound, highly permeable, and metabolically stable. Finally, compound 3 crosses the blood-brain barrier, and it improves memory, cognitive functions, and learning abilities of mice in a scopolamine model of dementia. Compound 3 is thus a promising advanced lead compound for the development of drugs for alleviating symptoms of cholinergic hypofunction in patients with advanced Alzheimer's disease.
N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: Potential multifunctional anti-Alzheimer's agents
Ko?ak, Urban,Knez, Damijan,Brus, Boris,Pi?lar, Anja,Kos, Janko,Gobec, Stanislav,Coquelle, Nicolas,Colletier, Jacques-Philippe,Nachon, Florian,Brazzolotto, Xavier
, p. 633 - 645 (2016/12/30)
In the brains of patients with Alzheimer's disease, the enzymatic activities of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer's disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines. All of these compounds inhibited hBChE with good selectivity over the related enzyme, acetylcholinesterase, and crossed the blood-brain barrier in a parallel artificial membrane permeation assay. The crystal structure of one of the inhibitors (compound 3) in complex with hBChE revealed its binding mode. Three compounds (4, 5, 6) showed concomitant inhibition of MAO-B. Additionally, the most potent hBChE inhibitor 7 and dual BChE and MAO-B inhibitor 6 were non-cytotoxic and protected neuronal SH-SY5Y cells from toxic amyloid β-peptide species.
PIPERIDINE AMIDES AS MODULATORS OF THE GHRELIN RECEPTOR
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Page/Page column 28, (2011/10/13)
Compounds of formula (I) or pharmaceutically acceptable salts thereof, are useful for the treatment of diabetes and obesity.
QUINAZOLINES USEFUL AS MODULATORS OF ION CHANNELS
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Page/Page column 279-280, (2008/06/13)
The present invention relates to compounds useful as inhibitors of voltage-gated sodium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
NOVEL COMPOUNDS WITH ANTIBACTERIAL ACTIVITY
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Page/Page column 21-22, (2010/02/06)
The invention relates to novel antibacterial compounds of formula (I).
Design and synthesis of potent and highly selective thrombin inhibitors
Hilpert,Ackermann,Banner,Gast,Gubernator,Hadvary,Labler,Muller,Schmid,Tschopp,Van de Waterbeemd
, p. 3889 - 3901 (2007/10/02)
Thrombin, a serine protease, plays a central role in the initiation and propagation of thrombotic events. An extensive search for new thrombin inhibitors was performed, using an unconventional approach. Screening of small basic molecules for binding in th
Guanidine derivatives compositions and use
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, (2008/06/13)
Compounds of the formula STR1 wherein L, M, R, T and X are set forth in the description, as well as hydrates or solvates thereof, which inhibit thrombin-induced platelet aggregation and clotting of fibrinogen in plasma, are described. The compounds of formula I are prepared by amidination or, depending on whether L is NH or O, by amide formation or esterification.
