- |||||||||| Cognex (tacrine) / Shionogi
Review, Journal: A Review on Recent Development of Novel Heterocycles as Acetylcholinesterase inhibitor for the treatment of Alzheimer's disease. (Pubmed Central) - Mar 16, 2023
In this review, we reported the recent development of novel heterocyclic compounds such as coumarin-benzotriazole hybrids, carbazole derivatives, tacrine conjugates, N-benzyl-piperidine-aryl-acyl hydrazones hybrid, spiropyrazoline derivatives, coumarin-dithiocarbamate hybrids, etc., as AChE inhibitors for the treatment of Alzheimer disease...Furthermore, most of the compounds show a low toxicity profile during in vivo studies. The results suggest that all the compounds constitute promising leads for the AChE targeted approach for Alzheimer's disease.
- |||||||||| Cognex (tacrine) / Shionogi
Journal: Sub-pocket-focused designing of tacrine derivatives as potential acetylcholinesterase inhibitors. (Pubmed Central) - Mar 14, 2023
Cytotoxic nature of these SPFTDs on HepG2 and Neuro-2a cell lines, diminishes the possibilities for future in vivo studies. However, the identification of these sub pockets and the SPFTDs paved a new way to the future drug discovery especially since AChE is one of the promising and approved drug targets in treatment of AD drug discovery.
- |||||||||| Amsidine (amsacrine) / Kyowa Kirin, Cognex (tacrine) / Shionogi
Journal: Acridine: A Scaffold for the development of drugs for Alzheimer's disease. (Pubmed Central) - Feb 7, 2023
Further research is required to evaluate the effectiveness of the acridine derivatives with various substitutions in the treatment of AD. In conclusion, our review will suggest the potentiality of the versatile acridine framework for drug designing and developing novel multi-target inhibitors for the Alzheimer's disease.
- |||||||||| Cognex (tacrine) / Shionogi
Review, Journal: Tacrine-Based Hybrids: Past, Present, and Future. (Pubmed Central) - Jan 22, 2023
However, its high potency in ChE inhibition, low molecular weight, and simple structure make THA a promising scaffold for developing multi-target agents. In this review, we summarized THA-based hybrids published from 2006 to 2022, thus providing an overview of strategies that have been used in drug design and approaches that have resulted in significant cognitive improvements and reduced hepatotoxicity.
- |||||||||| Cognex (tacrine) / Shionogi
Journal, IO biomarker: Rosmarinic acid potentiates and detoxifies tacrine in combination for Alzheimer's disease. (Pubmed Central) - Jan 8, 2023
Based on the findings, we propose that Ondansetron may have therapeutic applications in inhibiting cholinesterase, especially for BChE. The potential drug combination that combines rosmarinic acid with tacrine could reduce tacrine's hepatotoxicity as well as enhance its therapeutic effect on Alzheimer's disease.
- |||||||||| Cognex (tacrine) / Shionogi
Journal: Effects of L1 adhesion molecule agonistic mimetics on signal transduction in neuronal functions. (Pubmed Central) - Dec 22, 2022
Our findings indicates that L1 agonistic mimetics trigger the same cell signaling pathways underlying neurite outgrowth, but only the L1 mimetics tacrine, polydatin, trimebutine and honokiol trigger neuronal migration. In contrast, the mimetics crotamiton and duloxetine did not affect neuronal migration, thus limiting their use in increasing neuronal migration, leaving open the question of whether this is a desired or not desired feature in the adult.
- |||||||||| Cognex (tacrine) / Shionogi
Journal: Novel Dual AChE and ROCK2 Inhibitor Induces Neurogenesis via PTEN/AKT Pathway in Alzheimer's Disease Model. (Pubmed Central) - Dec 12, 2022
In silico analysis showed that TA8Amino can stably bind to the active site of ROCK2, and in vitro experiments in SH-SY5Y cells demonstrate that TA8Amino significantly reduced the expression of ROCK2 protein, contrasting with donepezil and tacrine. Therefore, these results provide important information on the mechanism underlying the action of TA8Amino with regard to multi-target activities.
- |||||||||| Cognex (tacrine) / Shionogi
Journal: Recent developments in tacrine-based hybrids as a therapeutic option for Alzheimer's disease. (Pubmed Central) - Dec 6, 2022
Here, tacrine-based derivatives including heterocyclic structures such as dihydroxypyridine, chromene, coumarin, pyrazole, triazole, tetrahydroquinolone, dipicolylamine, arylisoxazole were reported with promising anti-AD effects compared to tacrine. In vitro and in vivo assays showed that new tacrine-based hybrids, which are selective, neuroprotective, and non-hepatotoxic, might be considered as remarkable anti-AD drug candidates for further clinical studies.
- |||||||||| Cognex (tacrine) / Shionogi
Journal: Piperazine derivatives with potent drug moiety as efficient acetylcholinesterase, butyrylcholinesterase, and glutathione S-transferase inhibitors. (Pubmed Central) - Nov 25, 2022
Also, piperazine derivatives exhibited Ki values of 8.04 ± 5.73-61.94 ± 54.56, 0.24 ± 0.03-32.14 ± 16.20, and 7.73 ± 1.13-22.97 ± 9.10 µM toward AChE, BChE, and GST, respectively. Consequently, the inhibitory properties of the AChE/BChE and GST enzymes have been compared to Tacrine (for AChE and BChE) and Etacrynic acid (for GST).
- |||||||||| Cognex (tacrine) / Shionogi
Preclinical, Journal: An aqueous macerate of Ziziphus jujuba reduces long-term spatial memory impairment in D-galactose treated rats: role of anti-inflammatory pathways. (Pubmed Central) - Nov 22, 2022
Previous studies showed that a concoction of Ziziphus jujuba leaves possesses anti-amnesic effects in scopolamine-treated rats...Rats that developed memory impairment were treated with tacrine (10 mg/kg, p.o.), or aspirin (20 mg/kg, p.o.), or extract (41.5, 83, and 166 mg/kg, p.o.), once daily, for 14 days...Together, these results suggest that this aqueous extract Z. jujuba reduces long-term spatial memory impairment. This effect may be mediated in part by its anti-inflammatory activity.
- |||||||||| Cognex (tacrine) / Shionogi
Journal: Phytochemicals-based Therapeutics against Alzheimer's Disease: An Update. (Pubmed Central) - Nov 16, 2022
Phyto-chemicals derived from plants exhibit neuroprotection via targeting apoptosis, neurotrophic factor deficit, mitochondrial dysfunction, oxidative stress, and abnormal accumulation of proteins. Here, we discussed some of the neuroprotective phytochemicals used for the treatment of neurodegenerative diseases like AD and dementia.
- |||||||||| Cognex (tacrine) / Shionogi
Preclinical, Journal: Non-covalent acetylcholinesterase inhibitors: In vitro screening and molecular modeling for novel selective insecticides. (Pubmed Central) - Oct 26, 2022
In our work, fourteen compounds of 7-methoxytacrine-tacrine heterodimers were tested for their insecticidal effect...Docking studies were performed to predict the binding modes of selected compounds. K1328 and K1329 provided high HssAChE/AgAChE selectivity outperforming standard pesticides (carbofuran and bendiocarb), and thus can be considered as suitable lead structure for novel anticholinesterase insecticides.
- |||||||||| Cognex (tacrine) / Shionogi
Newly synthetised tacrine derivatives as potent inhibitors of NMDA receptors (Poster area [IN-PERSON]) - Oct 13, 2022 - Abstract #ECNP2022ECNP_967;
Our subsequent detailed electrophysiological analysis based on 5 different concentrations of selected compounds showed that selected compounds (4 and 5) strongly inhibited both GluN1/GluN2A and GluN1/GluN2B receptors; other compounds (7 and 23) more strongly inhibited GluN1/GluN2B receptors; or GluN1/GluN2A receptors (21 and 28). We further showed that at 10 µM concentration (measured at a membrane voltage of -60 mV), compounds 21 and 23 exhibited similar relative inhibition of GluN1/GluN2C (~30%) and GluN1/GluN2D (~25%) receptors as 7-MEOTA, whereas compounds 7, 28, 4 and 5 inhibited both GluN1/GluN2C and GluN1/GluN2D receptors with significantly lower potency compared to 7-MEOTA (p < 0.001, t test). Conclusion : Our Result s indicated that the development of novel 7-MEOTA derivatives with subunit-binding effects on NMDARs is one possible avenue for the future treatment of some central nervous system diseases associated with abnormal NMDAR regulation.
- |||||||||| ifenprodil tartrate / Chiba University Hospital
7-phenoxytacrine and its derivative potently inhibits the GluN1/GluN2B subtype of NMDA receptor via an ifenprodil-binding site (Poster area [IN-PERSON]) - Oct 13, 2022 - Abstract #ECNP2022ECNP_608;
We found that both GluN1-ΔATD/GluN2B-ΔATD and GluN1-Y109/GluN2B receptors showed a significant increase in IC50 values of both compounds (~10 µM at -60 mV; p < 0.001; t-test) compared to the wild-type GluN1/GluN2B subtype. Conclusion : Our Result s showed that both 7-PhO-THA and K1958 potently inhibit the GluN1/GluN2B subtype via the ifenprodil binding site and further exhibit less potent voltage-dependent blockade of both GluN1/GluN2A and GluN1/GluN2B subtypes. Thus, compared to THA, both 7-PhO-THA and K1958 have a unique mechanism of action for NMDAR inhibition.
- |||||||||| ifenprodil tartrate / Chiba University Hospital, Cognex (tacrine) / Shionogi
7-Phenoxytacrine and its derivatives effectively inhibit the GluN1/GluN2B subtype of the NMDA receptor (SDCC Halls B-H) - Oct 10, 2022 - Abstract #Neuroscience2022NEUROSCIENCE_7090;
Finally, we observed that two different derivatives of 7-PhO-THA, K1958, and K1959, exhibited similar interaction with the ifenprodil-binding site of the GluN1/GluN2B receptor when compared with 7-PhO-THA, but K1959 had a more profound voltage-dependent inhibitory effect at both GluN1/GluN2A and GluN1/GluN2B receptors. Together, our experimental data showed that 7-PhO-THA and its derivatives are promising compounds for further development.
- |||||||||| Cognex (tacrine) / Shionogi
Journal: Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif. (Pubmed Central) - Oct 7, 2022
The docking studies revealed precise binding modes between 6a, 6d, and 6h and hCA II, hCA I, and AChE, respectively. The results presented here might provide a solid basis for further investigation into more potent AChEIs and hCAIs.
- |||||||||| Cognex (tacrine) / Shionogi
Journal: Synthesis, characterization, Evaluation of Metabolic Enzyme Inhibitors and in silico Studies of Thymol Based 2-Amino Thiol and Sulfonic Acid Compounds. (Pubmed Central) - Sep 29, 2022
Acetazolamide was employed as the positive control for both hCA isoforms (K for hCA I 198.81 ± 14.13 nM and K for hCA II 211.42 ± 13.10 nM), and among the new compounds obtained, it was observed that there were compounds that were active at much lower nM levels...They inhibited AChE and BChE enzymes in the range of Ki 5.24 ± 2.27 (6c) - 48.44 ± 21.82 (4g) for AChE and 4.86 ± 0.64 (6c) - 51.75 ± 12.56 (4a) for BChE, and the results were compared with the standard inhibitor Tacrine (K: 14.20 ± 8.83 nM toward AChE and K: 3.39 ± 1.91 nM for BChE)...The molecular coupling scores of the compounds and the free binding energies calculated by MM/GBSA were found to be compatible. Examining the results obtained from this study shows that it may have the potential to develop new drugs to treat some global patients such as glaucoma and Alzheimer's disease (AD).
- |||||||||| Cognex (tacrine) / Shionogi
Journal: Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities. (Pubmed Central) - Sep 29, 2022
In all, compounds 7, 15, 20, 21, 23, and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride (15) has been identified as a permeable agent that shows a balanced pharmacological profile [IC (hAChE) = 1.472 ± 0.024 µM; IC (hBChE) = 0.659 ± 0.077 µM; IC (hMAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.
- |||||||||| Cognex (tacrine) / Shionogi
Review, Journal: Comprehensive Review on Natural Pharmacophore Tethered 1,2,3-Triazoles as Active Pharmaceuticals. (Pubmed Central) - Sep 23, 2022
Furthermore, the dual/multi-pharmacophores assimilated 1,2,3-triazoles have listed interesting biological activities that could be valuable as future drug leads. In addition, this comprehensive review can serve as a template for the development of new diverse scaffolds that will ensure for newl therapeutic approaches for the existing myriad diseases and disorders.
- |||||||||| Cognex (tacrine) / Shionogi
Review, Journal: Tacrine Derivatives in Neurological Disorders: Focus on Molecular Mechanisms and Neurotherapeutic Potential. (Pubmed Central) - Aug 30, 2022
A new paradigm for treating neurological diseases is presented in this review, which includes treatment strategies for Alzheimer's disease, as well as other neurological disorders like Parkinson's disease and the synthesis and biological properties of newly identified versatile tacrine analogues and hybrids. We have also shown that these analogues may have therapeutic promise in the treatment of neurological diseases in a variety of experimental systems.
- |||||||||| Cognex (tacrine) / Shionogi
Journal: Radiologist-Trained and -Tested (R2.2.4) Deep Learning Models for Identifying Anatomical Landmarks in Chest CT. (Pubmed Central) - Aug 27, 2022
We trained and tested (R2.2.4) two (R3-2) deep learning (DL) algorithms on a machine vision tool library platform (Cognex Vision Pro Deep Learning software) to recognize anatomic landmarks and classify chest CT as those with optimum, under-scanned, or over-scanned scan length...(3) The two DL models for lung apex and bases had high sensitivity, specificity, accuracy, and areas under the curve (AUC) for identifying under-scanning (100%, 99%, 99%, and 0.999 (95% CI 0.996-1.000)) and over-scanning (99%, 99%, 99%, and 0.998 (95%CI 0.992-1.000)). (4) Our DL models can accurately identify markers for missing anatomic coverage and over-scanning in chest CTs.
- |||||||||| Cognex (tacrine) / Shionogi
Journal: New Imaging Modality of COVID-19 Pneumonia Developed on the Basis of Alzheimer's Disease Research. (Pubmed Central) - Aug 22, 2022
On the basis of molecular modelling combined with in vitro studies, we unraveled which structural properties of the developed tacrine derivatives are crucial for high affinity toward acetylcholinesterase, whose increased levels in lung tissues in the course of coronavirus disease indicate the onset of pneumonia. The radiopharmaceutical [Ga]Ga-THP-NH(CH)Tac was ultimately selected due to its increased accuracy and improved sensitivity in PET imaging of lung tissue with high levels of acetylcholinesterase, and it may become a novel potential diagnostic modality for the determination of lung perfusion, including in inflammation after COVID-19.
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