920463-28-1Relevant academic research and scientific papers
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.
Straightforward synthesis of orthogonally protected piperidin-3- ylmethanamine and piperidin-4-ylmethanamine derivatives
Ko?ak, Urban,Brus, Boris,Gobec, Stanislav
, p. 2037 - 2039 (2014/04/03)
The 1,3- and 1,4-disubstituted piperidines are important building blocks in medicinal chemistry and drug discovery. We present the synthesis of orthogonally protected piperidin-3-ylmethanamine and piperidin-4-ylmethanamine derivatives from commercially available nipecotamide, isonipecotamide, nipecotic acid and isonipecotic acid. This is a straightforward two-step procedure that gives high overall yields. Purification of the intermediates using this procedure is not necessary, and the final compounds are purified by simple flash column chromatography.
