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Literature summary extracted from
- 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
| EC Number | Application | Comment | Organism |
|---|---|---|---|
| 3.1.1.8 | 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)
| EC Number | Crystallization (Comment) | Organism |
|---|---|---|
| 3.1.1.8 | 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
| EC Number | Inhibitors | Comment | Organism | Structure |
|---|---|---|---|---|
| 3.1.1.8 | (+/-)-6-bromo-N-((1-(2,3-dihydro-1H-inden-2-yl)-piperidin-3-yl)methyl)-N-(2-methoxyethyl)-2-naphthamide | - |
Homo sapiens |  |
| 3.1.1.8 | (+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-1-naphthamide | - |
Homo sapiens | |
| 3.1.1.8 | (+/-)-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 | |
| 3.1.1.8 | (+/-)-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 | |
| 3.1.1.8 | (+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(3-methoxypropyl)-2-naphthamide | - |
Homo sapiens | |
| 3.1.1.8 | (+/-)-N-((1-(benzo[d]thiazol-2-ylmethyl)piperidin-3-yl)methyl)-2-naphthamide | - |
Homo sapiens | |
| 3.1.1.8 | (+/-)-N-((1-benzylpiperidin-3-yl)methyl)-2-naphthamide | - |
Homo sapiens | |
| 3.1.1.8 | (+/-)-N-((1-benzylpiperidin-3-yl)methyl)-N-(2-methoxyethyl)-2-naphthamide | - |
Homo sapiens | |
| 3.1.1.8 | donepezil | - |
Homo sapiens | |
| 3.1.1.8 | galantamine | - |
Homo sapiens | |
| 3.1.1.8 | 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 | |
| 3.1.1.8 | N-((1-benzylpiperidin-4-yl)methyl)-N-(2-methoxyethyl)-2-naphthamide | - |
Homo sapiens | |
| 3.1.1.8 | N-[(1-benzylpiperidin-3-yl)methyl]-N-(2-methoxyethyl)naphthalene-2-sulfonamide | the inhibitor is highly selective for BChE versus acetylcholinesterase, AChE | Homo sapiens | |
| 3.1.1.8 | 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 | |
| 3.1.1.8 | rivastigmine | - |
Homo sapiens | |
| 3.1.1.8 | tacrine | - |
Homo sapiens | |
Natural Substrates/ Products (Substrates)
| EC Number | Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|---|
| 3.1.1.8 | butyrylcholine + H2O | Homo sapiens | - |
choline + butyrate | - |
? | |
| 3.1.1.8 | butyrylcholine + H2O | Rattus norvegicus | - |
choline + butyrate | - |
? | |
Organism
| EC Number | Organism | UniProt | Comment | Textmining |
|---|---|---|---|---|
| 3.1.1.8 | Homo sapiens | P06276 | - |
- |
| 3.1.1.8 | Rattus norvegicus | Q9JKC1 | - |
- |
Source Tissue
| EC Number | Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|---|
| 3.1.1.8 | amygdala | - |
Homo sapiens | - |
| 3.1.1.8 | brain | - |
Rattus norvegicus | - |
| 3.1.1.8 | 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 | - |
| 3.1.1.8 | glial cell | - |
Homo sapiens | - |
| 3.1.1.8 | neocortex | - |
Homo sapiens | - |
| 3.1.1.8 | neuron | - |
Homo sapiens | - |
| 3.1.1.8 | SH-SY5Y cell | - |
Homo sapiens | - |
| 3.1.1.8 | thalamus | - |
Homo sapiens | - |
Substrates and Products (Substrate)
| EC Number | Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|---|
| 3.1.1.8 | butyrylcholine + H2O | - |
Homo sapiens | choline + butyrate | - |
? | |
| 3.1.1.8 | butyrylcholine + H2O | - |
Rattus norvegicus | choline + butyrate | - |
? | |
| 3.1.1.8 | butyrylthiocholine + H2O | - |
Homo sapiens | thiocholine + butyrate | - |
? | |
| 3.1.1.8 | butyrylthiocholine + H2O | - |
Rattus norvegicus | thiocholine + butyrate | - |
? | |
Synonyms
| EC Number | Synonyms | Comment | Organism |
|---|---|---|---|
| 3.1.1.8 | BChE | - |
Homo sapiens |
| 3.1.1.8 | BChE | - |
Rattus norvegicus |
| 3.1.1.8 | butyrylcholinesterase | - |
Homo sapiens |
| 3.1.1.8 | butyrylcholinesterase | - |
Rattus norvegicus |
| 3.1.1.8 | HuBChE | - |
Homo sapiens |
Temperature Optimum [°C]
| EC Number | Temperature Optimum [°C] | Temperature Optimum Maximum [°C] | Comment | Organism |
|---|---|---|---|---|
| 3.1.1.8 | 25 | - |
assay at | Homo sapiens |
| 3.1.1.8 | 25 | - |
assay at | Rattus norvegicus |
pH Optimum
| EC Number | pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
|---|---|---|---|---|
| 3.1.1.8 | 8 | - |
assay at | Homo sapiens |
| 3.1.1.8 | 8 | - |
assay at | Rattus norvegicus |
Ki Value [mM]
| EC Number | Ki Value [mM] | Ki Value maximum [mM] | Inhibitor | Comment | Organism | Structure |
|---|---|---|---|---|---|---|
| 3.1.1.8 | additional information | - |
additional information | inhibition kinetics, thermodynamic analysis of binding, overview | Homo sapiens | |
| 3.1.1.8 | additional information | - |
additional information | inhibition kinetics, thermodynamic analysis of binding, overview | Rattus norvegicus |
IC50 Value
| EC Number | IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|---|
| 3.1.1.8 | 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 | |
| 3.1.1.8 | 0.00000491 | - |
pH 8.0, 25°C | Homo sapiens | N-[(1-benzylpiperidin-3-yl)methyl]-N-(2-methoxyethyl)naphthalene-2-sulfonamide | |
| 3.1.1.8 | 0.000012 | - |
pH 8.0, 25°C | Homo sapiens | tacrine | |
| 3.1.1.8 | 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 | |
| 3.1.1.8 | 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 | |
| 3.1.1.8 | 0.000067 | - |
pH 8.0, 25°C | Homo sapiens | (+/-)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-1-naphthamide | |
| 3.1.1.8 | 0.00023 | - |
pH 8.0, 25°C | Homo sapiens | (+/-)-N-((1-benzylpiperidin-3-yl)methyl)-N-(2-methoxyethyl)-2-naphthamide | |
| 3.1.1.8 | 0.00037 | - |
pH 8.0, 25°C | Homo sapiens | rivastigmine | |
| 3.1.1.8 | 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 | |
| 3.1.1.8 | 0.000632 | - |
pH 8.0, 25°C | Homo sapiens | (+/-)-N-((1-(benzo[d]thiazol-2-ylmethyl)piperidin-3-yl)methyl)-2-naphthamide | |
| 3.1.1.8 | 0.000702 | - |
pH 8.0, 25°C | Homo sapiens | N-((1-benzylpiperidin-4-yl)methyl)-N-(2-methoxyethyl)-2-naphthamide | |
| 3.1.1.8 | 0.001437 | - |
pH 8.0, 25°C | Homo sapiens | (+/-)-N-((1-benzylpiperidin-3-yl)methyl)-2-naphthamide | |
| 3.1.1.8 | 0.00714 | - |
pH 8.0, 25°C | Homo sapiens | donepezil | |
| 3.1.1.8 | 0.0191 | - |
pH 8.0, 25°C | Homo sapiens | galantamine | |
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