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Discovery of cyclic sulfone hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure-based design and in vivo reduction of amyloid β-peptides.

Rueeger H, Lueoend R, Rogel O, Rondeau JM, Möbitz H, Machauer R, Jacobson L, Staufenbiel M, Desrayaud S, Neumann U
J Med Chem 55 3364-86 (2012)
Related entries: 3pi5, 3qbh, 3veu, 3vg1, 4d83, 4d85, 4d88, 4d89, 4d8c

Cited: 28 times
EuropePMC logo PMID: 22380629

Abstract

Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC(50) values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 μmol/kg demonstrated significant reduction of brain Aβ levels.

Articles - 3vf3 mentioned but not cited (3)

  1. RepurposeVS: A Drug Repurposing-Focused Computational Method for Accurate Drug-Target Signature Predictions. Issa NT, Peters OJ, Byers SW, Dakshanamurthy S. Comb. Chem. High Throughput Screen. 18 784-794 (2015)
  2. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)
  3. Investigation of Potential Drug Targets for Cholesterol Regulation to Treat Alzheimer's Disease. Passero M, Zhai T, Huang Z. Int J Environ Res Public Health 20 6217 (2023)


Reviews citing this publication (7)

  1. BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease. Ghosh AK, Osswald HL. Chem Soc Rev 43 6765-6813 (2014)
  2. Advances in the identification of β-secretase inhibitors. Hamada Y, Kiso Y. Expert Opin Drug Discov 8 709-731 (2013)
  3. The structural evolution of β-secretase inhibitors: a focus on the development of small-molecule inhibitors. Butini S, Brogi S, Novellino E, Campiani G, Ghosh AK, Brindisi M, Gemma S. Curr Top Med Chem 13 1787-1807 (2013)
  4. New directions for protease inhibitors directed drug discovery. Hamada Y, Kiso Y. Biopolymers 106 563-579 (2016)
  5. Computer Aided Drug Design and its Application to the Development of Potential Drugs for Neurodegenerative Disorders. Baig MH, Ahmad K, Rabbani G, Danishuddin M, Choi I. Curr Neuropharmacol 16 740-748 (2018)
  6. Kitamura Electrophilic Fluorination Using HF as a Source of Fluorine. Han J, Butler G, Moriwaki H, Konno H, Soloshonok VA, Kitamura T. Molecules 25 (2020)
  7. Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer's Therapeutics. Mouchlis VD, Melagraki G, Zacharia LC, Afantitis A. Int J Mol Sci 21 (2020)

Articles citing this publication (18)

  1. Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid β-peptides. Rueeger H, Lueoend R, Machauer R, Veenstra SJ, Jacobson LH, Staufenbiel M, Desrayaud S, Rondeau JM, Möbitz H, Neumann U. Bioorg. Med. Chem. Lett. 23 5300-5306 (2013)
  2. Population PKPD modeling of BACE1 inhibitor-induced reduction in Aβ levels in vivo and correlation to in vitro potency in primary cortical neurons from mouse and guinea pig. Janson J, Eketjäll S, Tunblad K, Jeppsson F, Von Berg S, Niva C, Radesäter AC, Fälting J, Visser SA. Pharm. Res. 31 670-683 (2014)
  3. Catalytic asymmetric [3 + 3] annulation of cyclopropanes with mercaptoacetaldehyde. Fu X, Lin L, Xia Y, Zhou P, Liu X, Feng X. Org. Biomol. Chem. 14 5914-5917 (2016)
  4. Identifying natural compounds as multi-target-directed ligands against Alzheimer's disease: an in silico approach. Ambure P, Bhat J, Puzyn T, Roy K. J. Biomol. Struct. Dyn. 37 1282-1306 (2019)
  5. Microsecond molecular dynamics simulation of Aβ42 and identification of a novel dual inhibitor of Aβ42 aggregation and BACE1 activity. Wang YY, Li L, Chen TT, Chen WY, Xu YC. Acta Pharmacol. Sin. 34 1243-1250 (2013)
  6. Access to Highly Functionalized Sulfonated Cyclopentanes by Acid-Promoted Rauhut-Currier Reaction with Sulfinamides. Gigant N, Drège E, Retailleau P, Joseph D. Chemistry 21 15544-15547 (2015)
  7. Diastereoselective tandem reactions of substituted 3-sulfolenes with bis-vinyl ketones leading to highly functionalized bicyclic and tricyclic frameworks. Brant MG, Friedmann JN, Bohlken CG, Oliver AG, Wulff JE. Org. Biomol. Chem. 13 4581-4588 (2015)
  8. Multidirectional in vitro and in cellulo studies as a tool for identification of multi-target-directed ligands aiming at symptoms and causes of Alzheimer's disease. Szałaj N, Godyń J, Jończyk J, Pasieka A, Panek D, Wichur T, Więckowski K, Zaręba P, Bajda M, Pislar A, Malawska B, Sabate R, Więckowska A. J Enzyme Inhib Med Chem 35 1944-1952 (2020)
  9. Multitarget Approach to Drug Candidates against Alzheimer's Disease Related to AChE, SERT, BACE1 and GSK3β Protein Targets. Ivanova L, Karelson M, Dobchev DA. Molecules 25 (2020)
  10. A new benchmark illustrates that integration of geometric constraints inferred from enzyme reaction chemistry can increase enzyme active site modeling accuracy. Bertolani SJ, Siegel JB. PLoS ONE 14 e0214126 (2019)
  11. Catalyst free annulative thioboration of unfunctionalized olefins. Yang Z, Yang CH, Chen S, Chen X, Zhang L, Ren H. Chem. Commun. (Camb.) 53 12092-12095 (2017)
  12. Comparative QSAR studies using HQSAR, CoMFA, and CoMSIA methods on cyclic sulfone hydroxyethylamines as BACE1 inhibitors. Zhang S, Lin Z, Pu Y, Zhang Y, Zhang L, Zuo Z. Comput Biol Chem 67 38-47 (2017)
  13. Dirhodium Carboxylate Catalysts from 2-Fenchyloxy or 2-Menthyloxy Arylacetic Acids: Enantioselective C-H Insertion, Aromatic Addition and Oxonium Ylide Formation/Rearrangement. Buckley AM, Crowley DC, Brouder TA, Ford A, Rao Khandavilli UB, Lawrence SE, Maguire AR. ChemCatChem 13 4318-4324 (2021)
  14. Hybrid approach to sieve out natural compounds against dual targets in Alzheimer's Disease. Das S, Chakraborty S, Basu S. Sci Rep 9 3714 (2019)
  15. Modified Tacrine Derivatives as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease: Synthesis, Biological Evaluation, and Molecular Modeling Study. Fares S, El Husseiny WM, Selim KB, Massoud MAM. ACS Omega 8 26012-26034 (2023)
  16. Pharmacophore based 3D-QSAR modeling, virtual screening and docking for identification of potential inhibitors of β-secretase. Palakurti R, Vadrevu R. Comput Biol Chem 68 107-117 (2017)
  17. Sulfur-containing therapeutics in the treatment of Alzheimer's disease. Zhu H, Dronamraju V, Xie W, More SS. Med Chem Res 30 305-352 (2021)
  18. Synthesis of novel 4-methylthiocoumarin and comparison with conventional coumarin derivative as a multi-target-directed ligand in Alzheimer's disease. Kumar S, Tyagi YK, Kumar M, Kumar S. 3 Biotech 10 509 (2020)


Related citations provided by authors (1)

  1. Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors.. Rueeger H, Rondeau JM, McCarthy C, Möbitz H, Tintelnot-Blomley M, Neumann U, Desrayaud S Bioorg Med Chem Lett 21 1942-7 (2011)

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