4dh6 › Citations

Design and preparation of a potent series of hydroxyethylamine containing β-secretase inhibitors that demonstrate robust reduction of central β-amyloid.

Weiss MM, Williamson T, Babu-Khan S, Bartberger MD, Brown J, Chen K, Cheng Y, Citron M, Croghan MD, Dineen TA, Esmay J, Graceffa RF, Harried SS, Hickman D, Hitchcock SA, Horne DB, Huang H, Imbeah-Ampiah R, Judd T, Kaller MR, Kreiman CR, La DS, Li V, Lopez P, Louie S, Monenschein H, Nguyen TT, Pennington LD, Rattan C, San Miguel T, Sickmier EA, Wahl RC, Wen PH, Wood S, Xue Q, Yang BH, Patel VF, Zhong W
J Med Chem 55 9009-24 (2012)
Cited: 26 times
EuropePMC logo PMID: 22468639

Abstract

A series of potent hydroxyethyl amine (HEA) derived inhibitors of β-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS β-amyloid (Aβ) in Sprague-Dawley rats following oral administration.

Articles - 4dh6 mentioned but not cited (2)

  1. Coffee and caffeine potentiate the antiamyloidogenic activity of melatonin via inhibition of Aβ oligomerization and modulation of the Tau-mediated pathway in N2a/APP cells. Zhang LF, Zhou ZW, Wang ZH, Du YH, He ZX, Cao C, Zhou SF. Drug Des Devel Ther 9 241-272 (2015)
  2. Synthesis, Spectroscopic Identification and Molecular Docking of Certain N-(2-{[2-(1H-Indol-2-ylcarbonyl) Hydrazinyl](oxo)Acetylphenyl)Acetamides and N-[2-(2-{[2-(Acetylamino)Phenyl](oxo)Acetylhydrazinyl)-2-Oxoethyl]-1H-Indole-2-Carboxamides: New Antimicrobial Agents. Almutairi MS, Zakaria AS, Al-Wabli RI, Joe IH, Abdelhameed AS, Attia MI. Molecules 23 (2018)


Reviews citing this publication (8)

  1. BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease. Ghosh AK, Osswald HL. Chem Soc Rev 43 6765-6813 (2014)
  2. The use of spirocyclic scaffolds in drug discovery. Zheng Y, Tice CM, Singh SB. Bioorg. Med. Chem. Lett. 24 3673-3682 (2014)
  3. Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies. Nikolic K, Mavridis L, Djikic T, Vucicevic J, Agbaba D, Yelekci K, Mitchell JB. Front Neurosci 10 265 (2016)
  4. BACE1 as a therapeutic target in Alzheimer's disease: rationale and current status. Evin G, Hince C. Drugs Aging 30 755-764 (2013)
  5. Advances in the identification of β-secretase inhibitors. Hamada Y, Kiso Y. Expert Opin Drug Discov 8 709-731 (2013)
  6. 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)
  7. Cyclobutanes in Small-Molecule Drug Candidates. van der Kolk MR, Janssen MACH, Rutjes FPJT, Blanco-Ania D. ChemMedChem 17 e202200020 (2022)
  8. The emerging role of furin in neurodegenerative and neuropsychiatric diseases. Zhang Y, Gao X, Bai X, Yao S, Chang YZ, Gao G. Transl Neurodegener 11 39 (2022)

Articles citing this publication (16)

  1. A perspective on multi-target drug discovery and design for complex diseases. Ramsay RR, Popovic-Nikolic MR, Nikolic K, Uliassi E, Bolognesi ML. Clin Transl Med 7 3 (2018)
  2. Mechanistic insights into mode of action of potent natural antagonists of BACE-1 for checking Alzheimer's plaque pathology. Dhanjal JK, Goyal S, Sharma S, Hamid R, Grover A. Biochem. Biophys. Res. Commun. 443 1054-1059 (2014)
  3. Mechanistic pharmacokinetic-pharmacodynamic modeling of BACE1 inhibition in monkeys: development of a predictive model for amyloid precursor protein processing. Liu X, Wong H, Scearce-Levie K, Watts RJ, Coraggio M, Shin YG, Peng K, Wildsmith KR, Atwal JK, Mango J, Schauer SP, Regal K, Hunt KW, Thomas AA, Siu M, Lyssikatos J, Deshmukh G, Hop CE. Drug Metab Dispos 41 1319-1328 (2013)
  4. A tale of two drug targets: the evolutionary history of BACE1 and BACE2. Southan C, Hancock JM. Front Genet 4 293 (2013)
  5. Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer's Disease Dementia in Individuals With Mild Cognitive Impairment. Shen Y, Wang H, Sun Q, Yao H, Keegan AP, Mullan M, Wilson J, Lista S, Leyhe T, Laske C, Rujescu D, Levey A, Wallin A, Blennow K, Li R, Hampel H. Biol. Psychiatry 83 447-455 (2018)
  6. Design and synthesis of thiophene dihydroisoquinolines as novel BACE1 inhibitors. Xu YZ, Yuan S, Bowers S, Hom RK, Chan W, Sham HL, Zhu YL, Beroza P, Pan H, Brecht E, Yao N, Lougheed J, Yan J, Tam D, Ren Z, Ruslim L, Bova MP, Artis DR. Bioorg. Med. Chem. Lett. 23 3075-3080 (2013)
  7. Establishing the relationship between in vitro potency, pharmacokinetic, and pharmacodynamic parameters in a series of orally available, hydroxyethylamine-derived β-secretase inhibitors. Wood S, Wen PH, Zhang J, Zhu L, Luo Y, Babu-Khan S, Chen K, Pham R, Esmay J, Dineen TA, Kaller MR, Weiss MM, Hitchcock SA, Citron M, Zhong W, Hickman D, Williamson T. J Pharmacol Exp Ther 343 460-467 (2012)
  8. 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)
  9. Hydroxyethylamine-based inhibitors of BACE1: P₁-P₃ macrocyclization can improve potency, selectivity, and cell activity. Pennington LD, Whittington DA, Bartberger MD, Jordan SR, Monenschein H, Nguyen TT, Yang BH, Xue QM, Vounatsos F, Wahl RC, Chen K, Wood S, Citron M, Patel VF, Hitchcock SA, Zhong W. Bioorg. Med. Chem. Lett. 23 4459-4464 (2013)
  10. Biotransformation of two β-secretase inhibitors including ring opening and contraction of a pyrimidine ring. Lindgren A, Eklund G, Turek D, Malmquist J, Swahn BM, Holenz J, von Berg S, Karlström S, Bueters T. Drug Metab Dispos 41 1134-1147 (2013)
  11. Optimization of a Pyrimidinone Series for Selective Inhibition of Ca2+/Calmodulin-Stimulated Adenylyl Cyclase 1 Activity for the Treatment of Chronic Pain. Scott JA, Soto-Velasquez M, Hayes MP, LaVigne JE, Miller HR, Kaur J, Ejendal KFK, Watts VJ, Flaherty DP. J Med Chem 65 4667-4686 (2022)
  12. Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: prime side chromane-containing inhibitors. Ng RA, Sun M, Bowers S, Hom RK, Probst GD, John V, Fang LY, Maillard M, Gailunas A, Brogley L, Neitz RJ, Tung JS, Pleiss MA, Konradi AW, Sham HL, Dappen MS, Adler M, Yao N, Zmolek W, Nakamura D, Quinn KP, Sauer JM, Bova MP, Ruslim L, Artis DR, Yednock TA. Bioorg. Med. Chem. Lett. 23 4674-4679 (2013)
  13. Design of Curcumin and Flavonoid Derivatives with Acetylcholinesterase and Beta-Secretase Inhibitory Activities Using in Silico Approaches. Tran TS, Le MT, Tran TD, Tran TH, Thai KM. Molecules 25 (2020)
  14. Discovery of a Hydroxylamine-Based Brain-Penetrant EGFR Inhibitor for Metastatic Non-Small-Cell Lung Cancer. Hill J, Jones RM, Crich D. J Med Chem 66 15477-15492 (2023)
  15. 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)
  16. Synthesis, In Silico and In Vitro Evaluation for Acetylcholinesterase and BACE-1 Inhibitory Activity of Some N-Substituted-4-Phenothiazine-Chalcones. Tran TS, Le MT, Nguyen TC, Tran TH, Tran TD, Thai KM. Molecules 25 (2020)


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