Synthesis and biological evaluation of thieno[3,2-c]pyrazol-3-amine derivatives as potent glycogen synthase kinase 3β inhibitors for Alzheimer’s disease

References

• Patterson C, World Alzheimer report 2018. London: Alzheimer’s Disease International; 2018.
   Google Scholar
• Srivastava S, Ahmad R, Khare SK. Alzheimer's disease and its treatment by different approaches: A review. Eur J Med Chem 2021;216:1724.
   Web of Science ®Google Scholar
• Liu W, Liu X, Liu W, et al. Discovery of novel β-carboline derivatives as selective AChE inhibitors with GSK-3β inhibitory property for the treatment of Alzheimer's disease. Eur J Med Chem 2022; 229:114095.
   PubMed Web of Science ®Google Scholar
• Verma A, Kumar Waiker D, Bhardwaj B, et al. The molecular mechanism, targets, and novel molecules in the treatment of Alzheimer's disease. Bioorg Chem 2022;119:105562.
   PubMed Web of Science ®Google Scholar
• Syed YY. Sodium Oligomannate: First approval. Drugs 2020;80:441–4.
   PubMed Web of Science ®Google Scholar
• Dhillon S. Aducanumab: First approval. Drugs 2021;81:1437–43.
   PubMed Web of Science ®Google Scholar
• Wang K, Na L, Duan M. The pathogenesis mechanism, structure properties, potential drugs and therapeutic nanoparticles against the small oligomers of Amyloid-β. Curr Top Med Chem 2021;21:151–67.
   PubMed Web of Science ®Google Scholar
• Chen G-F, Xu T-H, Yan Y, et al. Amyloid beta: Structure, biology and structure-based therapeutic development. Acta Pharmacol Sin 2017;38:1205–35.
   PubMed Web of Science ®Google Scholar
• Anu Kunnath R, Subham D, Alex J, et al. Neurodegenerative pathways in Alzheimer's Disease: A Review. Curr Neuropharmacol 2021;19:679–92.
   PubMed Web of Science ®Google Scholar
• Tan CC, Zhang XY, Tan L, et al. Tauopathies: Mechanisms and therapeutic strategies. J Alzheimers Dis 2018;61:487–508.
   PubMed Web of Science ®Google Scholar
• Congdon EE, Sigurdsson EM. Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 2018;14:399–415.
   PubMed Web of Science ®Google Scholar
• Li Y, Jiao Q, Xu H, et al. Biometal dyshomeostasis and toxic metal accumulations in the development of Alzheimer’s disease. Front Mol Neurosci 2017;10:339.
   PubMed Web of Science ®Google Scholar
• Huang WJ, Zhang X, Chen WW. Role of oxidative stress in Alzheimer's disease. Biomed Rep 2016;4:519–22.
   PubMed Web of Science ®Google Scholar
• Wang T, Xu SF, Fan YG, et al. Iron pathophysiology in Alzheimer's Diseases. Adv Exp Med Biol 2019;1173:67–104.
   PubMed Web of Science ®Google Scholar
• Kinney JW, Bemiller SM, Murtishaw AS, et al. Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement (N Y) 2018;4:575–90.
   PubMedGoogle Scholar
• Tong BC, Wu AJ, Li M, et al. Calcium signaling in Alzheimer's disease & therapies. Biochim Biophys Acta Mol Cell Res 2018;1865:1745–60.
   PubMed Web of Science ®Google Scholar
• Gerakis Y, Hetz C. Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer's disease. Febs J 2018;285:995–1011.
   PubMed Web of Science ®Google Scholar
• Hill E, Wall MJ, Moffat KG, et al. Understanding the pathophysiological actions of tau oligomers: A critical review of current electrophysiological approaches. Front Mol Neurosci 2020;13:155.
   PubMed Web of Science ®Google Scholar
• Tripathi T, Kalita P. Synergistic effect of Amyloid-β and tau disrupts neural circuits. ACS Chem Neurosci 2019;10:1129–30.
   PubMed Web of Science ®Google Scholar
• Yin X, Qiu Y, Zhao C, et al. The role of amyloid-beta and tau in the early pathogenesis of Alzheimer's Disease. Med Sci Monit 2021;27:e933084.
   PubMed Web of Science ®Google Scholar
• He Z, Guo JL, McBride JD, et al. Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med 2018;24:29–38.
   PubMed Web of Science ®Google Scholar
• Bennett RE, DeVos SL, Dujardin S, et al. Enhanced tau aggregation in the presence of amyloid β. Am J Pathol 2017;187:1601–12.
   PubMed Web of Science ®Google Scholar
• Doble BW, Woodgett JR. Role of glycogen synthase kinase-3 in cell fate and epithelial-mesenchymal transitions. Cells Tissues Organs 2007;185:73–84.
   PubMed Web of Science ®Google Scholar
• La Pietra V, La Regina G, Coluccia A, et al. Design, synthesis, and biological evaluation of 1-phenylpyrazolo[3,4-e]pyrrolo[3,4-g]indolizine-4,6(1H,5H)-diones as new glycogen synthase kinase-3β inhibitors. J Med Chem 2013;56:10066–78.
   PubMed Web of Science ®Google Scholar
• Pei JJ, Braak E, Braak H, et al. Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes. J Neuropathol Exp Neurol 1999;58:1010–9.
   PubMed Web of Science ®Google Scholar
• Georgievska B, Sandin J, Doherty J, et al. AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans. J Neurochem 2013;125:446–56.
   PubMed Web of Science ®Google Scholar
• Iqbal K, Grundke-Iqbal I. Discoveries of tau, abnormally hyperphosphorylated tau and others of neurofibrillary degeneration: A personal historical perspective. J Alzheimers Dis 2006;9:219–42.
   PubMed Web of Science ®Google Scholar
• Wischik CM, Harrington CR, Storey JM. Tau-aggregation inhibitor therapy for Alzheimer's disease. Biochem Pharmacol 2014;88:529–39.
   PubMed Web of Science ®Google Scholar
• De Simone A, Tumiatti V, Andrisano V, et al. Glycogen synthase kinase 3β: A new gold rush in Anti-Alzheimer's Disease Multitarget Drug Discovery? J Med Chem 2021;64:26–41.
   PubMed Web of Science ®Google Scholar
• Llorens-Martin M, Jurado J, Avila J, et al. GSK-3β, a pivotal kinase in Alzheimer disease. Front Mol Neurosci 2014;7:46.
   PubMed Web of Science ®Google Scholar
• Forlenza OV, De-Paula VJR, Diniz BSO. Neuroprotective effects of lithium: Implications for the treatment of Alzheimer's disease and related neurodegenerative disorders. ACS Chem Neurosci 2014;5:443–50.
   PubMed Web of Science ®Google Scholar
• Wang H, Brown J, Martin M. Glycogen synthase kinase 3: A point of convergence for the host inflammatory response. Cytokine 2011;53:130–40.
   PubMed Web of Science ®Google Scholar
• Gómez-Sintes R, Hernández F, Lucas JJ, Avila J. er al. GSK-3 mouse models to study neuronal apoptosis and neurodegeneration. Front Mol Neurosci 2011;4:45.
   PubMed Web of Science ®Google Scholar
• Sayas CL, Ávila J. GSK-3 and tau: A key duet in Alzheimer’s disease. Cells 2021;10:721.
   PubMed Web of Science ®Google Scholar
• Ruiz A, Eldar-Finkelman SM. H. Glycogen synthase kinase-3 inhibitors: Preclinical and clinical focus on CNS-a decade onward. Front Mol Neurosci 2021;14:792364.
   PubMed Web of Science ®Google Scholar
• del T. S. Phase IIa clinical trial on Alzheimer’s disease with NP12, a GSK3 inhibitor. Alzheimers Dement 2010;6:S147.
   PubMedGoogle Scholar
• Bhat R, Xue Y, Berg S, et al. Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. J Biol Chem 2003;278:45937–45.
   PubMed Web of Science ®Google Scholar
• Berg S, Bergh M, Hellberg S, et al. Discovery of novel potent and highly selective glycogen synthase kinase-3β (GSK3β) inhibitors for Alzheimer's disease: design, synthesis, and characterization of pyrazines. J Med Chem 2012;55:9107–19.
   PubMed Web of Science ®Google Scholar
• Yao H, Uras G, Zhang P, et al. Discovery of novel tacrine-pyrimidone hybrids as potent dual AChE/GSK-3 inhibitors for the treatment of Alzheimer's Disease. J Med Chem 2021;64:7483–506.
   PubMedGoogle Scholar
• Sivaprakasam P, Han X, Civiello RL, et al. Discovery of new acylaminopyridines as GSK-3 inhibitors by a structure guided in-depth exploration of chemical space around a pyrrolopyridinone core. Bioorg Med Chem Lett 2015;25:1856–63.
   PubMed Web of Science ®Google Scholar
• Choi S, Park K, Seo HJ, et al. Preparation of pyrazole derivatives as TNIK, IKKε and TBK1 inhibitor and pharmaceutical composition comprising same. US20160289196. 2016.
   Google Scholar
• Ramurthy S, Pfister KB, Boyce RS, et al. Discovery and optimization of novel pyridines as highly potent and selective glycogen synthase kinase 3 inhibitors. Bioorg Med Chem Lett 2020;30:126930.
   PubMed Web of Science ®Google Scholar
• Liu SL, Wang C, Jiang T, et al. The role of CDK5 in Alzheimer's Disease. Mol Neurobiol 2016;53:4328–42.
   PubMed Web of Science ®Google Scholar
• Hanger DP, Anderton BH, Noble W. Tau phosphorylation: The therapeutic challenge for neurodegenerative disease. Trends Mol Med 2009;15:112–9.
   PubMed Web of Science ®Google Scholar
• Kimura T, Ishiguro K, Hisanaga S. Physiological and pathological phosphorylation of tau by CDK5. Front Mol Neurosci 2014;7:65.
   PubMed Web of Science ®Google Scholar
• Perez DI, Gil C, Martinez A. Protein kinases CK1 and CK2 as new targets for neurodegenerative diseases. Med Res Rev 2011;31:924–54.
   PubMed Web of Science ®Google Scholar
• Agholme L, Lindström T, Kågedal K, et al. An in vitro model for neuroscience: Differentiation of SH-SY5Y cells into cells with morphological and biochemical characteristics of mature neurons. J Alzheimers Dis 2010;20:1069–82.
   PubMed Web of Science ®Google Scholar
• Augello G, Emma MR, Cusimano A, et al. The role of GSK-3 in cancer immunotherapy: GSK-3 inhibitors as a new frontier in cancer treatment. Cells 2020;9:1427.
   PubMed Web of Science ®Google Scholar
• Beurel E, Grieco SF, Jope RS. Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases. Pharmacol Ther 2015;148:114–31.
   PubMed Web of Science ®Google Scholar
• Chalecka-Franaszek E, Chuang DM. Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. Proc Natl Acad Sci U S A 1999;96:8745–50.
   PubMed Web of Science ®Google Scholar
• Buttrick GJ, Wakefield JG. PI3-K and GSK-3: Akt-ing together with microtubules. Cell Cycle 2008;7:2621–5.
   PubMed Web of Science ®Google Scholar
• Ikeda S, Kishida S, Yamamoto H, et al. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin . Embo J 1998;17:1371–84.
   PubMed Web of Science ®Google Scholar
• Wu D, Pan W. GSK3: A multifaceted kinase in Wnt signaling. Trends Biochem Sci 2010;35:161–8.
   PubMed Web of Science ®Google Scholar
• Stamos JL, Weis WI. The β-catenin destruction complex. Cold Spring Harb Perspect Biol 2013;5:a007898.
   PubMed Web of Science ®Google Scholar
• MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases . Dev Cell 2009;17:9–26.
   PubMed Web of Science ®Google Scholar
• Salcedo-Tello P, Ortiz-Matamoros A, Arias C. GSK3 function in the brain during development, neuronal plasticity, and neurodegeneration. Int J Alzheimers Dis 2011;2011:189728.
   PubMedGoogle Scholar
• Skardelly M, Gaber K, Schwarz J, et al. Neuroprotective effects of the beta-catenin stabilization in an oxygen- and glucose-deprived human neural progenitor cell culture system. Int J Dev Neurosci 2011;29:543–7.
   PubMed Web of Science ®Google Scholar
• Jin N, Zhu H, Liang X, et al. Sodium selenate activated Wnt/β-catenin signaling and repressed amyloid-β formation in a triple transgenic mouse model of Alzheimer's disease. Exp Neurol 2017;297:36–49.
   PubMed Web of Science ®Google Scholar
• Toledo EM, Inestrosa NC. Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer's disease. Mol Psychiatry 2010;15:272–85,
   PubMed Web of Science ®Google Scholar
• Lu W, Yamamoto V, Ortega B, et al. Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth. Cell 2004;119:97–108.
   PubMed Web of Science ®Google Scholar
• Lin CC, Chou CH, Howng SL, et al. GSKIP, an inhibitor of GSK3beta, mediates the N-cadherin/beta-catenin pool in the differentiation of SH-SY5Y cells. J Cell Biochem 2009;108:1325–36.
   PubMed Web of Science ®Google Scholar
• Yap AS, Brieher WM, Pruschy M, et al. Lateral clustering of the adhesive ectodomain: A fundamental determinant of cadherin function. Curr Biol 1997;7:308–15.
   PubMed Web of Science ®Google Scholar
• González JF, Alcántara AR, Doadrio AL, et al. Developments with multi-target drugs for Alzheimer's disease: an overview of the current discovery approaches. Expert Opin Drug Discov 2019;14:879–91.
   PubMed Web of Science ®Google Scholar
• Shi X-L, Wu J-D, Liu P, et al. Synthesis and evaluation of novel GSK-3β inhibitors as multifunctional agents against Alzheimer's disease. Eur J Med Chem 2019;167:211–25.
   PubMed Web of Science ®Google Scholar
• Moradi HR, Hajali V, Khaksar Z, et al. The next step of neurogenesis in the context of Alzheimer's disease. Mol Biol Rep 2021;48:5647–60.
   PubMed Web of Science ®Google Scholar
• Jaworski T, Banach-Kasper E, Gralec K. GSK-3β at the intersection of neuronal plasticity and neurodegeneration. Neural Plast 2019;2019:4209475.
   PubMed Web of Science ®Google Scholar
• Giese KP. GSK-3: A key player in neurodegeneration and memory. IUBMB Life 2009;61:516–21.
   PubMed Web of Science ®Google Scholar
• Benowitz LI, Routtenberg A. GAP-43: An intrinsic determinant of neuronal development and plasticity. Trends Neurosci 1997;20:84–91.
   PubMed Web of Science ®Google Scholar
• Kawasaki A, Okada M, Tamada A, et al. Growth cone phosphoproteomics reveals that GAP-43 phosphorylated by JNK is a marker of axon growth and regeneration. iScience 2018;4:190–203.
   PubMed Web of Science ®Google Scholar
• Knoepfler PS, Cheng PF, Eisenman RN. N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. Genes Dev 2002;16:2699–712.
   PubMed Web of Science ®Google Scholar
• Nothias F, Vernier P, von Boxberg Y, et al. Modulation of NCAM polysialylation is associated with morphofunctional modifications in the hypothalamo-neurohypophysial system during lactation. Eur J Neurosci 1997;9:1553–65.
   PubMed Web of Science ®Google Scholar
• Sánchez Martin C, Ledesma D, Dotti CG, et al. Microtubule-associated protein-2 located in growth regions of rat hippocampal neurons is highly phosphorylated at its proline-rich region. Neuroscience 2000;101:885–93.
   PubMed Web of Science ®Google Scholar
• Rodriguez-Jimenez FJ, Vilches A, Perez-Arago MA, et al. Activation of neurogenesis in multipotent stem cells cultured in vitro and in the spinal cord tissue after severe injury by inhibition of glycogen synthase kinase-3. Neurotherapeutics 2021;18:515–33.
   PubMed Web of Science ®Google Scholar
• De Simone A, La Pietra V, Betari N, et al. Discovery of the first-in-class GSK-3β/HDAC dual inhibitor as disease-modifying agent to combat Alzheimer’s disease. ACS Med Chem Lett 2019;10:469–74.
   PubMed Web of Science ®Google Scholar
• Shi XL, Yan N, Cui YJ, et al. A unique GSK-3β inhibitor B10 has a direct effect on Aβ, targets tau and metal dyshomeostasis, and promotes neuronal neurite outgrowth. Cells 2020;9:649.
   PubMed Web of Science ®Google Scholar
• Pettersen EF, Goddard TD, Huang CC, et al. UCSF Chimera-a visualization system for exploratory research and analysis. J Comput Chem 2004;25:1605–12.
   PubMed Web of Science ®Google Scholar
• Maestro, version 11.9.011; Schrödinger, LLC, New York, NY, 2019.
   Google Scholar