Literature summary for 3.1.1.8 extracted from

Kosak, U.; Brus, B.; Knez, D.; Zakelj, S.; Trontelj, J.; Pislar, A.; Sink, R.; Jukic, M.; Zivin, M.; Podkowa, A.; Nachon, F.; Brazzolotto, X.; Stojan, J.; Kos, J.; Coquelle, N.; Salat, K.; Colletier, J.P.; Gobec, S.
The magic of crystal structure-based inhibitor optimization development of a butyrylcholinesterase inhibitor with picomolar affinity and in vivo activity (2018), J. Med. Chem., 61, 119-139 .

Application

Application	Comment	Organism
drug development	enzyme BChE is a promising drug target in advanced Alzheimer's disease. (+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide 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	Homo sapiens

Crystallization (Commentary)

Crystallization (Comment)	Organism
purified enzyme in complex with inhibitor (+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide, hanging drop vapour diffusion method, preincubation of 0.5 mM (+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide dichloride in 1% dimethylsulfoxide aqueous solution with the enzyme solution (0.090 mM) for 3 h, X-ray diffraction structure determination and analysis at 2.1 A resolution, modeling	Homo sapiens

Crystallization (Comment)

Organism

purified enzyme in complex with inhibitor (+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide, hanging drop vapour diffusion method, preincubation of 0.5 mM (+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide dichloride in 1% dimethylsulfoxide aqueous solution with the enzyme solution (0.090 mM) for 3 h, X-ray diffraction structure determination and analysis at 2.1 A resolution, modeling

Homo sapiens

Inhibitors

Inhibitors	Comment	Organism
(+/-)-6-bromo-N-((1-(2,3-dihydro-1H-inden-2-yl)-piperidin-3-yl)methyl)-N-(2-methoxyethyl)-2-naphthamide	-	Homo sapiens
(+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-1-naphthamide	-	Homo sapiens
(+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide	the inhibitor is highly selective for BChE versus acetylcholinesterase, AChE, and shows selective reversible huBChE inhibition in the picomolar concentration range. Enzyme-binding crystal structure determination and analysis, overview. The compound has a picomolar inhibition constant versus BChE due to strong cation-Pi interactions, as revealed by the solved crystal structure of its complex with human BChE. Additionally, the inhibitor inhibits BChE ex vivo and is noncytotoxic. In vitro pharmacokinetic experiments show that (+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide is highly protein-bound, highly permeable, and metabolically stable. (+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide crosses the blood-brain barrier and improves memory, cognitive functions, and learning abilities of mice in a scopolamine model of dementia. (+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide 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	Homo sapiens
(+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide	inhibition of BChE in rat brain slices, low cytotoxicity, favorable in vitro pharmacokinetics, and proven penetration into the brain. The brain-to-blood plasma ratio of (+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide is 1.47	Rattus norvegicus
(+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(3-methoxypropyl)-2-naphthamide	-	Homo sapiens
(+/-)-N-((1-(benzo[d]thiazol-2-ylmethyl)piperidin-3-yl)methyl)-2-naphthamide	-	Homo sapiens
(+/-)-N-((1-benzylpiperidin-3-yl)methyl)-2-naphthamide	-	Homo sapiens
(+/-)-N-((1-benzylpiperidin-3-yl)methyl)-N-(2-methoxyethyl)-2-naphthamide	-	Homo sapiens
donepezil	-	Homo sapiens
galantamine	-	Homo sapiens
additional information	structure-based drug discovery approach is used to develop potent, selective, and reversible human butyrylcholinesterase (BChE) inhibitors, crystal structure-based inhibitor optimization. Synthesis of class VIII Inhibitors. Competitive single-step inhibition mechanism with slow association. In vitro permeability assay with Caco-2 cells	Homo sapiens
N-((1-benzylpiperidin-4-yl)methyl)-N-(2-methoxyethyl)-2-naphthamide	-	Homo sapiens
N-[(1-benzylpiperidin-3-yl)methyl]-N-(2-methoxyethyl)naphthalene-2-sulfonamide	the inhibitor is highly selective for BChE versus acetylcholinesterase, AChE	Homo sapiens
N-[[1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl]methyl]-N-(2-methoxyethyl)naphthalene-2-carboxamide	the inhibitor is highly selective for BChE versus acetylcholinesterase, AChE. It is a potent, selective, and reversible slow tight-binding inhibitor of human BChE	Homo sapiens
rivastigmine	-	Homo sapiens
tacrine	-	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
butyrylcholine + H2O	Homo sapiens	-	choline + butyrate	-	?
butyrylcholine + H2O	Rattus norvegicus	-	choline + butyrate	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P06276	-	-
Rattus norvegicus	Q9JKC1	-	-

Source Tissue

Source Tissue	Comment	Organism	Textmining
amygdala	-	Homo sapiens	-
brain	-	Rattus norvegicus	-
brain	the enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease. BChE activity is mainly associated with glial cells, as well as with vascular and neuronal structures, with BChE-positive neurons defined for the thalamus, neocortex, and amygdala	Homo sapiens	-
glial cell	-	Homo sapiens	-
neocortex	-	Homo sapiens	-
neuron	-	Homo sapiens	-
SH-SY5Y cell	-	Homo sapiens	-
thalamus	-	Homo sapiens	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.
butyrylcholine + H2O	-	Homo sapiens	choline + butyrate	-	?
butyrylcholine + H2O	-	Rattus norvegicus	choline + butyrate	-	?
butyrylthiocholine + H2O	-	Homo sapiens	thiocholine + butyrate	-	?
butyrylthiocholine + H2O	-	Rattus norvegicus	thiocholine + butyrate	-	?

Synonyms

Synonyms	Comment	Organism
BChE	-	Homo sapiens
BChE	-	Rattus norvegicus
butyrylcholinesterase	-	Homo sapiens
butyrylcholinesterase	-	Rattus norvegicus
HuBChE	-	Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
25	-	assay at	Homo sapiens
25	-	assay at	Rattus norvegicus

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
8	-	assay at	Homo sapiens
8	-	assay at	Rattus norvegicus

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism	Structure
additional information	-	additional information	inhibition kinetics, thermodynamic analysis of binding, overview	Homo sapiens
additional information	-	additional information	inhibition kinetics, thermodynamic analysis of binding, overview	Rattus norvegicus

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor
0.00000103	-	pH 8.0, 25°C	Homo sapiens	(+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide
0.00000491	-	pH 8.0, 25°C	Homo sapiens	N-[(1-benzylpiperidin-3-yl)methyl]-N-(2-methoxyethyl)naphthalene-2-sulfonamide
0.000012	-	pH 8.0, 25°C	Homo sapiens	tacrine
0.0000213	-	pH 8.0, 25°C	Homo sapiens	N-[[1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl]methyl]-N-(2-methoxyethyl)naphthalene-2-carboxamide
0.00003824	-	pH 8.0, 25°C	Homo sapiens	(+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(3-methoxypropyl)-2-naphthamide
0.000067	-	pH 8.0, 25°C	Homo sapiens	(+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-1-naphthamide
0.00023	-	pH 8.0, 25°C	Homo sapiens	(+/-)-N-((1-benzylpiperidin-3-yl)methyl)-N-(2-methoxyethyl)-2-naphthamide
0.00037	-	pH 8.0, 25°C	Homo sapiens	rivastigmine
0.00041	-	pH 8.0, 25°C	Homo sapiens	(+/-)-6-bromo-N-((1-(2,3-dihydro-1H-inden-2-yl)-piperidin-3-yl)methyl)-N-(2-methoxyethyl)-2-naphthamide
0.000632	-	pH 8.0, 25°C	Homo sapiens	(+/-)-N-((1-(benzo[d]thiazol-2-ylmethyl)piperidin-3-yl)methyl)-2-naphthamide
0.000702	-	pH 8.0, 25°C	Homo sapiens	N-((1-benzylpiperidin-4-yl)methyl)-N-(2-methoxyethyl)-2-naphthamide
0.001437	-	pH 8.0, 25°C	Homo sapiens	(+/-)-N-((1-benzylpiperidin-3-yl)methyl)-2-naphthamide
0.00714	-	pH 8.0, 25°C	Homo sapiens	donepezil
0.0191	-	pH 8.0, 25°C	Homo sapiens	galantamine