cas 135632-53-0, 4-(Boc-Aminomethyl)piperidine

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The Magic of Crystal Structure-Based Inhibitor Optimization: Development of a Butyrylcholinesterase Inhibitor with Picomolar Affinity and in Vivo Activity
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.
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
supporting information
p. 119 - 139
(2018/01/01)

N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: Potential multifunctional anti-Alzheimer's agents
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.
Ko?ak, Urban,Knez, Damijan,Brus, Boris,Pi?lar, Anja,Kos, Janko,Gobec, Stanislav,Coquelle, Nicolas,Colletier, Jacques-Philippe,Nachon, Florian,Brazzolotto, Xavier
supporting information
p. 633 - 645
(2016/12/30)

SUBSTITUTED PYRIDOPYRAZINES AS NOVEL SYK INHIBITORS
Provided are pyridopyrazine compounds of formula (1), pharmaceutical compositions thereof and methods of use therefore, wherein R1, R2, R3, R4 and m are as defined in the specification.
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Paragraph 0158; 0159

(2014/05/08)

Autotaxin inhibitors
The present invention relates to novel compounds that are autotaxin inhibitors, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in diseases and disorders mediated by autotaxin.
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Page/Page column

(2014/06/25)

SUBSTITUTED PYRIDOPYRAZINES AS NOVEL SYK INHIBITORS
Provided are certain pyridopyrazine compounds, pharmaceutical compositions thereof and methods of use therefor.
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Page/Page column 34-35

(2013/02/27)

Collection of traceable compounds and uses thereof
The use of a collection of compounds of general formula (I), wherein: n is 0 or 1; p represents an integer between 1 and 6; r represents an integer between 1 and 12; R1 and R′1 represent in particular a hydrogen atom; R2 represents an amino acid side chain or an amino acid derivative; R3 represents a group derived from a carboxylic acid, bearing a basic entity; R4 represents in particular an alkyl group containing 1 to 10 carbon atoms; and A represents a hydrogen atom, a protecting group or a tracing group, in particular a fluorophor, a coloring agent or a quencher, for determining, through binding studies, ligands of receptors whose ligand is unknown or whose ligand useful for carrying out specific affinity binding assays is unknown.
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(2010/07/06)

Pyrimidine compounds
This invention relates to a method for treating inflammatory diseases or immune diseases, developmental or degenerative diseases, or tissue injuries. The method includes administering to a subject in need thereof an effective amount of one or more compounds of formula (I). Each variable in this formula is defined in the specification.
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Page/Page column 108-109

(2008/06/13)

NOVEL TRICYCLIC PIPERIDINYL COMPOUNDS USEFUL AS INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
Novel tricyclic compounds of formula (1.0) or a pharmaceutically acceptable salt or solvate thereof, wherein: one of a, b, c, and d represents N or NR, wherein R is O-, -CH3 or -(CH2)nCO2H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR or CR; or each of a, b, c and d is independently selected from CR or CR; each R and each R is independently selected from H, halo, -CR3, -OR, -COR, -SR, -S(O)tR (wherein t is 0, 1 or 2), -SCN, -N(R)2, -NRR, -NO2, -OC(O)R, -CO2R, -OCO2R, -CN, -NHC(O)R, -NHSO2R, -CONHR, -CONHCH2CH2OH, -NRCOOR, -SRC(O)OR, -SRN(R); n is 0 (zero), 1, 2, 3, 4, 5 or 6; T is -CO-; -SO-; -SO2-; or -CRR-; Z represents alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, -OR, -SR, -CRR, -NRR, formulae (i), (ii), (iii), (iv), (v) and (vi). Pharmaceutical compositions are disclosed which are inhibitors of the enzyme, farnesyl protein transferase. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering the novel tricyclic compound to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human.
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Page/Page column 68

(2008/06/13)

Amino acid derivatives with renin-inhibiting properties, a process for the preparation thereof, agents containing these, and the use thereof
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(2008/06/13)

Sulfonamide compounds, compositions and method of use
Certain substituted sulfonamide quinolines and isoquinolines are disclosed having anti-allergic activity. A preferred use is for the treatment of chronic obstructive lung disease, and in particular, asthma.
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(2008/06/13)