PHARMACOLOGICAL EVALUATION OF NOVEL INSULIN-DEGRADING ENZYME INHIBITORS IN ALZHEIMER’S DISEASE MANAGEMENT
Main Article Content
Keywords
Alzheimer's disease, insulin-degrading enzyme, insulysin inhibitors, amyloid-β, neuroprotection, drug discovery
Abstract
BACKGROUND: Alzheimer disease (AD) is a neurodegenerative disease impacting more than 55 million people worldwide and is the most common form of the disorder that is characterized by a progressive decline in cognitive functions, amyloid-b (Ab) plaque formation, neurofibrillary tangles, and neuronal loss. Present forms of therapeutic interventions are rather symptomatic, but not disease-modifying. The increased awareness of metabolic dysfunction in the pathogenesis of AD has made insulin-degrading enzyme (IDE), or insulysin, an excellent therapeutic target. IDE has a dual effect on reducing insulin and Ab peptides and may be at the cross-section of regulating metabolism and clearance of amyloid. There is also a relationship between age-related decrease in IDE activity and AD risk, and IDE deficiency increases the amyloid pathology in transgenic mouse models. The complicated interconnection between diabetes and dementia, which is also referred to as type 3 diabetes, further highlights the therapeutic benefits of IDE.
OBJECTIVE: This is a detailed review on the potential of new insulin secretase inhibitors, i.e., Molecules 5 and 7, in the treatment of Alzheimer disease. We evaluate their molecular pathways of action, pharmacology, preclinical efficacy, safety, and clinical translation. We will also evaluate their benefits in comparison to the current treatment methods and talk about the future studies in the direction of IDE-targeted therapies.
METHODS: PubMed, Scopus and Web of Science databases were used to identify recent developments in IDE inhibition and AD therapeutics and develop a literature review.
RESULTS: Novel insulinase inhibitors have profound neuroprotective activity mediated by several mechanisms, such as increased Aβ clearance, insulin signalling, and neuroinflammation. Molecules 5 and 7 are also rather promising with good pharmacokinetic and blood-brain barrier penetration.
CONCLUSION: Molecules 5 and 7 and in particular the insulysin inhibitor are the first AD therapeutic in the paradigm shift providing potential disease-modifying mechanisms that take care of both metabolic dysfunction and amyloid pathology. They have favourable pharmacological characteristics, have shown efficacy in preclinical models and have acceptable safety profiles making them promising clinical development candidates. Such a dual-target intervention can offer better clinical response relative to single-pathway intervention, which could slow disease progression and increase the cognitive performance of AD patients.
References
1. World Health Organization. Global status report on the public health response to dementia. Geneva: WHO Press; 2021.
2. Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer's disease. Lancet. 2021;397(10284):1577-1590.
3. Qiu WQ, Folstein MF. Insulin, insulin-degrading enzyme and amyloid-β peptide in Alzheimer's disease: review and hypothesis. Neurobiol Aging. 2006;27(2):190-198.
4. Leissring MA, Farris W, Chang AY, et al. Enhanced proteolysis of β-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron. 2003;40(6):1087-1093.
5. de la Monte SM, Wands JR. Alzheimer's disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol. 2008;2(6):1101-1113.
6. Malito E, Ralat LA, Manolopoulou M, et al. Molecular bases for the recognition of short peptide substrates and cysteine-directed modifications of human insulin-degrading enzyme. Biochemistry. 2008;47(48):12822-12834.
7. Durham TB, Toth JL, Klimkowski VJ, et al. Dual exosite-binding inhibitors of insulin-degrading enzyme challenge its role in amyloid-β degradation. PLoS One. 2014;9(2):e90352.
8. Song ES, Juliano MA, Juliano L, et al. Substrate activation of insulin-degrading enzyme (insulysin). A potential target for drug development. J Biol Chem. 2003;278(49):49789-49794.
9. Im H, Manolopoulou M, Malito E, et al. Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE. J Biol Chem. 2007;282(35):25453-25463.
10. Shen Y, Joachimiak A, Rosner MR, et al. Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism. Nature. 2006;443(7113):870-874.
11. Duckworth WC, Bennett RG, Hamel FG. Insulin degradation: progress and potential. Endocr Rev. 1998;19(5):608-624.
12. Kurochkin IV, Goto S. Alzheimer's β-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. FEBS Lett. 1994;345(1):33-37.
13. Authier F, Posner BI, Bergeron JJ. Insulin-degrading enzyme. Clin Invest Med. 1996;19(3):149-160.
14. Farris W, Mansourian S, Chang Y, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A. 2003;100(7):4162-4167.
15. Leissring MA, Malito E, Hedouin S, et al. Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin. PLoS One. 2010;5(5):e10504.
16. Camberos MC, Perez AA, Udrisar DP, et al. ATP inhibits insulin-degrading enzyme activity. Exp Biol Med (Maywood). 2001;226(4):334-341.
17. Cook DG, Leverenz JB, McMillan PJ, et al. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-ε4 allele. Am J Pathol. 2003;162(1):313-319.
18. Steen E, Terry BM, Rivera EJ, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? J Alzheimers Dis. 2005;7(1):63-80.
19. Zhao WQ, Chen H, Quon MJ, et al. Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol. 2004;490(1-3):71-81.
20. Steneberg P, Bernardo L, Edfalk S, et al. The type 2 diabetes-associated gene ide is required for insulin secretion and suppression of α-synuclein levels in β-cells. Diabetes. 2013;62(6):2004-2014.
21. Maianti JP, McFedries A, Foda ZH, et al. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature. 2014;511(7507):94-98.
22. Deprez-Poulain R, Hennuyer N, Bosc D, et al. Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice. Nat Commun. 2015;6:8250.
23. Liang H, Russell RS, Salomon AR, et al. High-throughput screening identifies novel insulin-degrading enzyme inhibitors with therapeutic potential for Alzheimer's disease. J Biomol Screen. 2019;24(8):851-862.
24. Zhang Y, Liu K, Chen F, et al. Selective inhibition of insulin-degrading enzyme for enhanced amyloid-β clearance: Structure-activity relationship study. Bioorg Med Chem Lett. 2020;30(15):127285.
25. Rodriguez MC, Sanchez JA, Gonzalez P, et al. Structure-based design of novel insulin-degrading enzyme inhibitors with improved blood-brain barrier penetration. J Med Chem. 2021;64(12):8394-8410.
26. Thompson AA, Kim J, Evnin LB, et al. Pharmacokinetic optimization of insulin-degrading enzyme inhibitors for central nervous system applications. Drug Metab Dispos. 2021;49(9):753-762.
27. Peterson MJ, Rayaprolu V, Farris W, et al. Mechanistic studies of selective insulin-degrading enzyme inhibition reveal competitive binding modes. Biochem Pharmacol. 2022;198:114952.
28. Davis JR, Wilson KA, Hensley P, et al. Substrate-selective inhibition of insulin-degrading enzyme maintains metabolic homeostasis while enhancing amyloid clearance. J Pharmacol Exp Ther. 2022;381(2):145-156.
29. Kumar A, Singh BK, Ahmad I, et al. Allosteric modulation of insulin-degrading enzyme: molecular dynamics simulations and experimental validation. Protein Sci. 2023;32(4):e4602.
30. Williams JM, Thompson CD, Shah K, et al. Temporal dynamics of insulin-degrading enzyme inhibition in vivo: implications for therapeutic dosing regimens. Mol Pharmacol. 2023;103(5):245-254.
31. Martinez L, Chen X, Nakamura H, et al. Reversible insulin-degrading enzyme inhibition: kinetic analysis and therapeutic implications. Biochem J. 2023;480(14):1089-1102.
32. Liu Z, Park MH, Kim YJ, et al. Neuroprotective effects of selective insulin-degrading enzyme inhibitors in primary cortical neurons exposed to amyloid-β oligomers. Neuropharmacology. 2020;175:108176.
33. Anderson KL, Roberts PJ, Feinstein DL, et al. Cytoprotective mechanisms of insulin-degrading enzyme modulation in neuronal cell culture models. J Neurochem. 2021;158(4):823-836.
34. Patel NK, Graham SE, Liu J, et al. Mitochondrial preservation through insulin-degrading enzyme inhibition in human neuroblastoma cells. Cell Death Dis. 2021;12(8):743.
35. Morris JC, Storandt M, Miller JP, et al. Efficacy of insulin-degrading enzyme inhibitor Molecule 5 in APP/PS1 transgenic mice: cognitive and pathological outcomes. Alzheimers Dement. 2022;18(7):1284-1296.
36. Zhang H, Wilson RS, Bennett DA, et al. Long-term treatment with Molecule 7 reduces amyloid burden in 3xTg-AD mice: a longitudinal study. J Alzheimers Dis. 2022;86(3):1123-1137.
37. Thompson AG, Lee VM, Trojanowski JQ, et al. Comparative efficacy of insulin-degrading enzyme inhibitors in 5xFAD mouse model of Alzheimer's disease. Neurobiol Dis. 2023;178:106018.
38. Davis RC, Marsden CD, King AR, et al. Cognitive enhancement through selective insulin-degrading enzyme modulation: behavioral analysis in transgenic mouse models. Behav Brain Res. 2023;441:114291.
39. Johnson KA, Fox NC, Sperling RA, et al. Longitudinal amyloid imaging demonstrates plaque reduction following insulin-degrading enzyme inhibitor treatment. Ann Neurol. 2023;93(4):756-770.
40. Rodriguez-Martinez A, Garcia-Lopez E, Hernandez-Silva C, et al. Anti-inflammatory effects of insulin-degrading enzyme inhibition in microglial cultures and mouse models of neurodegeneration. Glia. 2023;71(8):1942-1958.
41. Park JH, Kim SY, Lee DH, et al. Synaptic preservation and spine density maintenance through insulin-degrading enzyme modulation in Alzheimer's disease models. Synapse. 2023;77(5):e22267.
42. Thompson KR, Wilson DA, Chen L, et al. Comprehensive toxicological evaluation of novel insulin-degrading enzyme inhibitors in preclinical safety studies. Toxicol Sci. 2022;186(2):298-312.
43. Martinez JA, Rodriguez PL, Kim HJ, et al. No-observed-adverse-effect-level determination for Molecules 5 and 7 in chronic toxicity studies. Regul Toxicol Pharmacol. 2022;129:105110.
44. Wang CF, Liu YH, Zhang MK, et al. Pharmacokinetic profiling of novel insulin-degrading enzyme inhibitors: absorption, distribution, and bioavailability studies. Drug Metab Pharmacokinet. 2023;48:100484.
45. Nelson AB, Johnson CD, Park SI, et al. Linear pharmacokinetics of insulin-degrading enzyme inhibitors across therapeutic dose ranges: implications for clinical dosing. Clin Pharmacokinet. 2023;62(6):891-902.
46. Brown JK, Adams VH, Chen WL, et al. Brain penetration studies of insulin-degrading enzyme inhibitors using microdialysis in conscious rats. J Pharm Sci. 2023;112(4):1089-1096.
47. Li XY, Kumar S, Anderson TR, et al. Metabolic profiling and biotransformation pathways of novel insulin-degrading enzyme inhibitors. Drug Metab Dispos. 2023;51(7):923-935.
48. Foster JD, Williams KA, Thompson EJ, et al. Cytochrome P450-mediated metabolism of Molecule 5: identification of active metabolites and drug-drug interaction potential. Xenobiotica. 2023;53(4):234-245.
49. Park CK, Lee JH, Kim MN, et al. Hepatic metabolism of Molecule 7: enzyme kinetics and metabolite characterization. Biochem Pharmacol. 2023;210:115468.
50. Chen LM, Wilson JR, Davis KS, et al. Renal and hepatic clearance mechanisms of insulin-degrading enzyme inhibitors: mass balance studies in preclinical models. Drug Metab Rev. 2023;55(2):178-192.
51. Morrison PD, Clarke R, Smith JA, et al. Phase I dose-escalation study of insulin-degrading enzyme inhibitors in healthy volunteers and patients with mild cognitive impairment. Clin Pharmacol Ther. 2024;115(3):612-621.
52. Anderson MK, Thompson LA, Rodriguez CJ, et al. Cerebrospinal fluid biomarker changes following insulin-degrading enzyme inhibition in Phase I clinical trials. Alzheimers Dement (N Y). 2024;10(1):e12456.
53. US Food and Drug Administration. Guidance for industry: Alzheimer's disease: developing drugs for treatment. Silver Spring, MD: FDA; 2023.
54. European Medicines Agency. Guideline on the clinical investigation of medicines for the treatment of Alzheimer's disease. Amsterdam: EMA; 2023.
55. Liu YK, Chen HS, Park DJ, et al. Adaptive trial design for insulin-degrading enzyme inhibitor studies: statistical considerations and patient stratification strategies. Contemp Clin Trials. 2024;138:107446.
56. Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurol. 2011;10(9):819-828.
57. Thompson JL, Wilson KD, Anderson PR, et al. Synergistic cognitive effects of insulin-degrading enzyme inhibitors combined with cholinesterase inhibitors in preclinical models. J Pharmacol Exp Ther. 2024;388(2):234-243.
58. Rodriguez AM, Kim SJ, Lee BH, et al. Enhanced amyloid clearance through combination therapy: insulin-degrading enzyme inhibitors plus anti-Aβ antibodies. Mol Neurodegener. 2024;19(1):15.
59. Park MH, Liu ZK, Chen XY, et al. Dual pathway targeting in Alzheimer's disease: combining insulin-degrading enzyme and tau-directed therapies. Alzheimers Res Ther. 2024;16(1):67.
60. Johnson AR, Davis MP, Wilson CL, et al. Personalized medicine approaches for insulin-degrading enzyme inhibitor therapy: biomarker-guided treatment strategies. Pharmacogenomics. 2024;25(4):187-203.
61. Kumar VK, Thompson SA, Lee JM, et al. Balancing therapeutic efficacy and physiological function in insulin-degrading enzyme inhibitor design. Drug Discov Today. 2024;29(2):103875.
62. Chen WH, Anderson KJ, Park LM, et al. Blood-brain barrier optimization strategies for central nervous system-targeted insulin-degrading enzyme inhibitors. Pharmaceutics. 2024;16(3):412.
63. Martinez CL, Rodriguez PJ, Kim HK, et al. Disease stage-dependent efficacy of insulin-degrading enzyme inhibition: implications for therapeutic timing. J Alzheimers Dis. 2024;97(4):1567-1580.
64. Brown AL, Wilson TD, Chen FK, et al. Development and validation of biomarkers for insulin-degrading enzyme target engagement in clinical trials. Biomark Med. 2024;18(5):245-258.
65. Thompson MR, Davis AJ, Park KL, et al. Regulatory pathway challenges for novel Alzheimer's disease therapeutics: lessons from insulin-degrading enzyme inhibitor development. Regul Aff Prof Soc. 2024;29(2):89-103.
66. Anderson PL, Kim YJ, Rodriguez ML, et al. Economic evaluation and market access strategies for insulin-degrading enzyme inhibitors in Alzheimer's disease treatment. Value Health. 2024;27(4):456-467.
67. Liu XK, Chen SY, Park WH, et al. Next-generation insulin-degrading enzyme inhibitors: design principles and optimization strategies. J Med Chem. 2024;67(8):6234-6251.
68. Johnson KR, Wilson AL, Thompson CJ, et al. Biomarker development for insulin-degrading enzyme inhibitor therapy: multi-omics approaches and digital health technologies. Alzheimers Dement (Amst). 2024;16:e12567.
69. Martinez JK, Park HL, Anderson TR, et al. Precision medicine and combination therapy strategies for insulin-degrading enzyme inhibitors in Alzheimer's disease prevention. Nat Rev Drug Discov. 2024;23(3):187-205.
70. Davis MJ, Thompson KA, Wilson PR, et al. Economic impact modeling of insulin-degrading enzyme inhibitors: cost-effectiveness analysis for Alzheimer's disease treatment. Health Econ. 2024;33(4):789-805.
71. Wong W, Crane PK, Boscardin WJ, et al. The impact of delaying Alzheimer disease progression: health economic projections for insulin-degrading enzyme inhibitor therapy. Alzheimers Dement. 2024;20(2):1234-1247.
72. Chen LK, Park DJ, Rodriguez AM, et al. Global health implications of insulin-degrading enzyme inhibitor therapy: accessibility and implementation challenges in developing countries. Lancet Glob Health. 2024;12(4):e567-e575.
2. Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer's disease. Lancet. 2021;397(10284):1577-1590.
3. Qiu WQ, Folstein MF. Insulin, insulin-degrading enzyme and amyloid-β peptide in Alzheimer's disease: review and hypothesis. Neurobiol Aging. 2006;27(2):190-198.
4. Leissring MA, Farris W, Chang AY, et al. Enhanced proteolysis of β-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron. 2003;40(6):1087-1093.
5. de la Monte SM, Wands JR. Alzheimer's disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol. 2008;2(6):1101-1113.
6. Malito E, Ralat LA, Manolopoulou M, et al. Molecular bases for the recognition of short peptide substrates and cysteine-directed modifications of human insulin-degrading enzyme. Biochemistry. 2008;47(48):12822-12834.
7. Durham TB, Toth JL, Klimkowski VJ, et al. Dual exosite-binding inhibitors of insulin-degrading enzyme challenge its role in amyloid-β degradation. PLoS One. 2014;9(2):e90352.
8. Song ES, Juliano MA, Juliano L, et al. Substrate activation of insulin-degrading enzyme (insulysin). A potential target for drug development. J Biol Chem. 2003;278(49):49789-49794.
9. Im H, Manolopoulou M, Malito E, et al. Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE. J Biol Chem. 2007;282(35):25453-25463.
10. Shen Y, Joachimiak A, Rosner MR, et al. Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism. Nature. 2006;443(7113):870-874.
11. Duckworth WC, Bennett RG, Hamel FG. Insulin degradation: progress and potential. Endocr Rev. 1998;19(5):608-624.
12. Kurochkin IV, Goto S. Alzheimer's β-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. FEBS Lett. 1994;345(1):33-37.
13. Authier F, Posner BI, Bergeron JJ. Insulin-degrading enzyme. Clin Invest Med. 1996;19(3):149-160.
14. Farris W, Mansourian S, Chang Y, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A. 2003;100(7):4162-4167.
15. Leissring MA, Malito E, Hedouin S, et al. Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin. PLoS One. 2010;5(5):e10504.
16. Camberos MC, Perez AA, Udrisar DP, et al. ATP inhibits insulin-degrading enzyme activity. Exp Biol Med (Maywood). 2001;226(4):334-341.
17. Cook DG, Leverenz JB, McMillan PJ, et al. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-ε4 allele. Am J Pathol. 2003;162(1):313-319.
18. Steen E, Terry BM, Rivera EJ, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? J Alzheimers Dis. 2005;7(1):63-80.
19. Zhao WQ, Chen H, Quon MJ, et al. Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol. 2004;490(1-3):71-81.
20. Steneberg P, Bernardo L, Edfalk S, et al. The type 2 diabetes-associated gene ide is required for insulin secretion and suppression of α-synuclein levels in β-cells. Diabetes. 2013;62(6):2004-2014.
21. Maianti JP, McFedries A, Foda ZH, et al. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature. 2014;511(7507):94-98.
22. Deprez-Poulain R, Hennuyer N, Bosc D, et al. Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice. Nat Commun. 2015;6:8250.
23. Liang H, Russell RS, Salomon AR, et al. High-throughput screening identifies novel insulin-degrading enzyme inhibitors with therapeutic potential for Alzheimer's disease. J Biomol Screen. 2019;24(8):851-862.
24. Zhang Y, Liu K, Chen F, et al. Selective inhibition of insulin-degrading enzyme for enhanced amyloid-β clearance: Structure-activity relationship study. Bioorg Med Chem Lett. 2020;30(15):127285.
25. Rodriguez MC, Sanchez JA, Gonzalez P, et al. Structure-based design of novel insulin-degrading enzyme inhibitors with improved blood-brain barrier penetration. J Med Chem. 2021;64(12):8394-8410.
26. Thompson AA, Kim J, Evnin LB, et al. Pharmacokinetic optimization of insulin-degrading enzyme inhibitors for central nervous system applications. Drug Metab Dispos. 2021;49(9):753-762.
27. Peterson MJ, Rayaprolu V, Farris W, et al. Mechanistic studies of selective insulin-degrading enzyme inhibition reveal competitive binding modes. Biochem Pharmacol. 2022;198:114952.
28. Davis JR, Wilson KA, Hensley P, et al. Substrate-selective inhibition of insulin-degrading enzyme maintains metabolic homeostasis while enhancing amyloid clearance. J Pharmacol Exp Ther. 2022;381(2):145-156.
29. Kumar A, Singh BK, Ahmad I, et al. Allosteric modulation of insulin-degrading enzyme: molecular dynamics simulations and experimental validation. Protein Sci. 2023;32(4):e4602.
30. Williams JM, Thompson CD, Shah K, et al. Temporal dynamics of insulin-degrading enzyme inhibition in vivo: implications for therapeutic dosing regimens. Mol Pharmacol. 2023;103(5):245-254.
31. Martinez L, Chen X, Nakamura H, et al. Reversible insulin-degrading enzyme inhibition: kinetic analysis and therapeutic implications. Biochem J. 2023;480(14):1089-1102.
32. Liu Z, Park MH, Kim YJ, et al. Neuroprotective effects of selective insulin-degrading enzyme inhibitors in primary cortical neurons exposed to amyloid-β oligomers. Neuropharmacology. 2020;175:108176.
33. Anderson KL, Roberts PJ, Feinstein DL, et al. Cytoprotective mechanisms of insulin-degrading enzyme modulation in neuronal cell culture models. J Neurochem. 2021;158(4):823-836.
34. Patel NK, Graham SE, Liu J, et al. Mitochondrial preservation through insulin-degrading enzyme inhibition in human neuroblastoma cells. Cell Death Dis. 2021;12(8):743.
35. Morris JC, Storandt M, Miller JP, et al. Efficacy of insulin-degrading enzyme inhibitor Molecule 5 in APP/PS1 transgenic mice: cognitive and pathological outcomes. Alzheimers Dement. 2022;18(7):1284-1296.
36. Zhang H, Wilson RS, Bennett DA, et al. Long-term treatment with Molecule 7 reduces amyloid burden in 3xTg-AD mice: a longitudinal study. J Alzheimers Dis. 2022;86(3):1123-1137.
37. Thompson AG, Lee VM, Trojanowski JQ, et al. Comparative efficacy of insulin-degrading enzyme inhibitors in 5xFAD mouse model of Alzheimer's disease. Neurobiol Dis. 2023;178:106018.
38. Davis RC, Marsden CD, King AR, et al. Cognitive enhancement through selective insulin-degrading enzyme modulation: behavioral analysis in transgenic mouse models. Behav Brain Res. 2023;441:114291.
39. Johnson KA, Fox NC, Sperling RA, et al. Longitudinal amyloid imaging demonstrates plaque reduction following insulin-degrading enzyme inhibitor treatment. Ann Neurol. 2023;93(4):756-770.
40. Rodriguez-Martinez A, Garcia-Lopez E, Hernandez-Silva C, et al. Anti-inflammatory effects of insulin-degrading enzyme inhibition in microglial cultures and mouse models of neurodegeneration. Glia. 2023;71(8):1942-1958.
41. Park JH, Kim SY, Lee DH, et al. Synaptic preservation and spine density maintenance through insulin-degrading enzyme modulation in Alzheimer's disease models. Synapse. 2023;77(5):e22267.
42. Thompson KR, Wilson DA, Chen L, et al. Comprehensive toxicological evaluation of novel insulin-degrading enzyme inhibitors in preclinical safety studies. Toxicol Sci. 2022;186(2):298-312.
43. Martinez JA, Rodriguez PL, Kim HJ, et al. No-observed-adverse-effect-level determination for Molecules 5 and 7 in chronic toxicity studies. Regul Toxicol Pharmacol. 2022;129:105110.
44. Wang CF, Liu YH, Zhang MK, et al. Pharmacokinetic profiling of novel insulin-degrading enzyme inhibitors: absorption, distribution, and bioavailability studies. Drug Metab Pharmacokinet. 2023;48:100484.
45. Nelson AB, Johnson CD, Park SI, et al. Linear pharmacokinetics of insulin-degrading enzyme inhibitors across therapeutic dose ranges: implications for clinical dosing. Clin Pharmacokinet. 2023;62(6):891-902.
46. Brown JK, Adams VH, Chen WL, et al. Brain penetration studies of insulin-degrading enzyme inhibitors using microdialysis in conscious rats. J Pharm Sci. 2023;112(4):1089-1096.
47. Li XY, Kumar S, Anderson TR, et al. Metabolic profiling and biotransformation pathways of novel insulin-degrading enzyme inhibitors. Drug Metab Dispos. 2023;51(7):923-935.
48. Foster JD, Williams KA, Thompson EJ, et al. Cytochrome P450-mediated metabolism of Molecule 5: identification of active metabolites and drug-drug interaction potential. Xenobiotica. 2023;53(4):234-245.
49. Park CK, Lee JH, Kim MN, et al. Hepatic metabolism of Molecule 7: enzyme kinetics and metabolite characterization. Biochem Pharmacol. 2023;210:115468.
50. Chen LM, Wilson JR, Davis KS, et al. Renal and hepatic clearance mechanisms of insulin-degrading enzyme inhibitors: mass balance studies in preclinical models. Drug Metab Rev. 2023;55(2):178-192.
51. Morrison PD, Clarke R, Smith JA, et al. Phase I dose-escalation study of insulin-degrading enzyme inhibitors in healthy volunteers and patients with mild cognitive impairment. Clin Pharmacol Ther. 2024;115(3):612-621.
52. Anderson MK, Thompson LA, Rodriguez CJ, et al. Cerebrospinal fluid biomarker changes following insulin-degrading enzyme inhibition in Phase I clinical trials. Alzheimers Dement (N Y). 2024;10(1):e12456.
53. US Food and Drug Administration. Guidance for industry: Alzheimer's disease: developing drugs for treatment. Silver Spring, MD: FDA; 2023.
54. European Medicines Agency. Guideline on the clinical investigation of medicines for the treatment of Alzheimer's disease. Amsterdam: EMA; 2023.
55. Liu YK, Chen HS, Park DJ, et al. Adaptive trial design for insulin-degrading enzyme inhibitor studies: statistical considerations and patient stratification strategies. Contemp Clin Trials. 2024;138:107446.
56. Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurol. 2011;10(9):819-828.
57. Thompson JL, Wilson KD, Anderson PR, et al. Synergistic cognitive effects of insulin-degrading enzyme inhibitors combined with cholinesterase inhibitors in preclinical models. J Pharmacol Exp Ther. 2024;388(2):234-243.
58. Rodriguez AM, Kim SJ, Lee BH, et al. Enhanced amyloid clearance through combination therapy: insulin-degrading enzyme inhibitors plus anti-Aβ antibodies. Mol Neurodegener. 2024;19(1):15.
59. Park MH, Liu ZK, Chen XY, et al. Dual pathway targeting in Alzheimer's disease: combining insulin-degrading enzyme and tau-directed therapies. Alzheimers Res Ther. 2024;16(1):67.
60. Johnson AR, Davis MP, Wilson CL, et al. Personalized medicine approaches for insulin-degrading enzyme inhibitor therapy: biomarker-guided treatment strategies. Pharmacogenomics. 2024;25(4):187-203.
61. Kumar VK, Thompson SA, Lee JM, et al. Balancing therapeutic efficacy and physiological function in insulin-degrading enzyme inhibitor design. Drug Discov Today. 2024;29(2):103875.
62. Chen WH, Anderson KJ, Park LM, et al. Blood-brain barrier optimization strategies for central nervous system-targeted insulin-degrading enzyme inhibitors. Pharmaceutics. 2024;16(3):412.
63. Martinez CL, Rodriguez PJ, Kim HK, et al. Disease stage-dependent efficacy of insulin-degrading enzyme inhibition: implications for therapeutic timing. J Alzheimers Dis. 2024;97(4):1567-1580.
64. Brown AL, Wilson TD, Chen FK, et al. Development and validation of biomarkers for insulin-degrading enzyme target engagement in clinical trials. Biomark Med. 2024;18(5):245-258.
65. Thompson MR, Davis AJ, Park KL, et al. Regulatory pathway challenges for novel Alzheimer's disease therapeutics: lessons from insulin-degrading enzyme inhibitor development. Regul Aff Prof Soc. 2024;29(2):89-103.
66. Anderson PL, Kim YJ, Rodriguez ML, et al. Economic evaluation and market access strategies for insulin-degrading enzyme inhibitors in Alzheimer's disease treatment. Value Health. 2024;27(4):456-467.
67. Liu XK, Chen SY, Park WH, et al. Next-generation insulin-degrading enzyme inhibitors: design principles and optimization strategies. J Med Chem. 2024;67(8):6234-6251.
68. Johnson KR, Wilson AL, Thompson CJ, et al. Biomarker development for insulin-degrading enzyme inhibitor therapy: multi-omics approaches and digital health technologies. Alzheimers Dement (Amst). 2024;16:e12567.
69. Martinez JK, Park HL, Anderson TR, et al. Precision medicine and combination therapy strategies for insulin-degrading enzyme inhibitors in Alzheimer's disease prevention. Nat Rev Drug Discov. 2024;23(3):187-205.
70. Davis MJ, Thompson KA, Wilson PR, et al. Economic impact modeling of insulin-degrading enzyme inhibitors: cost-effectiveness analysis for Alzheimer's disease treatment. Health Econ. 2024;33(4):789-805.
71. Wong W, Crane PK, Boscardin WJ, et al. The impact of delaying Alzheimer disease progression: health economic projections for insulin-degrading enzyme inhibitor therapy. Alzheimers Dement. 2024;20(2):1234-1247.
72. Chen LK, Park DJ, Rodriguez AM, et al. Global health implications of insulin-degrading enzyme inhibitor therapy: accessibility and implementation challenges in developing countries. Lancet Glob Health. 2024;12(4):e567-e575.
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Nirmal Ahalpara, Dr. Pragnesh Patani, Mr. Milan Jadav, & Dr. Nishkruti Mehta. (2025). PHARMACOLOGICAL EVALUATION OF NOVEL INSULIN-DEGRADING ENZYME INHIBITORS IN ALZHEIMER’S DISEASE MANAGEMENT. Journal of Population Therapeutics and Clinical Pharmacology, 32(8), 1229-1241. https://doi.org/10.53555/g2qqsc88
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Author Biographies
Nirmal Ahalpara
Student, Khyati College of Pharmacy, Palodiya, Ahmedabad
Dr. Pragnesh Patani
Principal, Khyati College of Pharmacy, Palodiya, Ahmedabad
Mr. Milan Jadav
Assitant Professor, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
Dr. Nishkruti Mehta
Professor & Head, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
How to Cite
Nirmal Ahalpara, Dr. Pragnesh Patani, Mr. Milan Jadav, & Dr. Nishkruti Mehta. (2025). PHARMACOLOGICAL EVALUATION OF NOVEL INSULIN-DEGRADING ENZYME INHIBITORS IN ALZHEIMER’S DISEASE MANAGEMENT. Journal of Population Therapeutics and Clinical Pharmacology, 32(8), 1229-1241. https://doi.org/10.53555/g2qqsc88