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Design and synthesis of β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of β-amyloid peptides.

Swahn BM, Kolmodin K, Karlström S, von Berg S, Söderman P, Holenz J, Berg S, Lindström J, Sundström M, Turek D, Kihlström J, Slivo C, Andersson L, Pyring D, Rotticci D, Ohberg L, Kers A, Bogar K, von Kieseritzky F, Bergh M, Olsson LL, Janson J, Eketjäll S, Georgievska B, Jeppsson F, Fälting J
J Med Chem 55 9346-61 (2012)
Cited: 30 times
EuropePMC logo PMID: 22924815

Abstract

The evaluation of a series of aminoisoindoles as β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clinical candidate drug for Alzheimer's disease, (S)-32 (AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain reduction of Aβ40, is discussed. Due to the basic nature of these compounds, they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 and (R)-41 showing large in vitro margins with BACE1 cell IC(50) values of 8.6 and 0.16 nM, respectively, and hERG IC(50) values of 16 and 2.8 μM, respectively. Several compounds were advanced into pharmacodynamic studies and demonstrated significant reduction of β-amyloid peptides in mouse brain following oral dosing.

Reviews citing this publication (8)

  1. The evolution of amidine-based brain penetrant BACE1 inhibitors. Oehlrich D, Prokopcova H, Gijsen HJ. Bioorg Med Chem Lett 24 2033-2045 (2014)
  2. Stepping closer to treating Alzheimer's disease patients with BACE1 inhibitor drugs. Yan R. Transl Neurodegener 5 13 (2016)
  3. Structure-based ligand design to overcome CYP inhibition in drug discovery projects. Brändén G, Sjögren T, Schnecke V, Xue Y. Drug Discov Today 19 905-911 (2014)
  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. Inhibitors of BACE for treating Alzheimer's disease: a fragment-based drug discovery story. Stamford A, Strickland C. Curr Opin Chem Biol 17 320-328 (2013)
  6. Critical thinking on amyloid-beta-targeted therapy: challenges and perspectives. Sun BL, Chen Y, Fan DY, Zhu C, Zeng F, Wang YJ. Sci China Life Sci 64 926-937 (2021)
  7. Small-molecule drugs development for Alzheimer's disease. Yao W, Yang H, Yang J. Front Aging Neurosci 14 1019412 (2022)
  8. N-(3-(2-amino-6,6-difluoro-4,4a,5,6,7,7a-hexahydro-cyclopenta[e][1,3]oxazin-4-yl)-phenyl)-amides as BACE1 inhibitors: a patent evaluation of WO2013041499. Dessolin J. Expert Opin Ther Pat 24 239-242 (2014)

Articles citing this publication (22)

  1. A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-β and neuroinflammation in APP transgenic mice. Neumann U, Rueeger H, Machauer R, Veenstra SJ, Lueoend RM, Tintelnot-Blomley M, Laue G, Beltz K, Vogg B, Schmid P, Frieauff W, Shimshek DR, Staufenbiel M, Jacobson LH. Mol Neurodegener 10 44 (2015)
  2. Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. Jeppsson F, Eketjäll S, Janson J, Karlström S, Gustavsson S, Olsson LL, Radesäter AC, Ploeger B, Cebers G, Kolmodin K, Swahn BM, von Berg S, Bueters T, Fälting J. J Biol Chem 287 41245-41257 (2012)
  3. AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics. Eketjäll S, Janson J, Kaspersson K, Bogstedt A, Jeppsson F, Fälting J, Haeberlein SB, Kugler AR, Alexander RC, Cebers G. J Alzheimers Dis 50 1109-1123 (2016)
  4. Revisiting the peripheral sink hypothesis: inhibiting BACE1 activity in the periphery does not alter β-amyloid levels in the CNS. Georgievska B, Gustavsson S, Lundkvist J, Neelissen J, Eketjäll S, Ramberg V, Bueters T, Agerman K, Juréus A, Svensson S, Berg S, Fälting J, Lendahl U. J Neurochem 132 477-486 (2015)
  5. AZ-4217: a high potency BACE inhibitor displaying acute central efficacy in different in vivo models and reduced amyloid deposition in Tg2576 mice. Eketjäll S, Janson J, Jeppsson F, Svanhagen A, Kolmodin K, Gustavsson S, Radesäter AC, Eliason K, Briem S, Appelkvist P, Niva C, Berg AL, Karlström S, Swahn BM, Fälting J. J Neurosci 33 10075-10084 (2013)
  6. Ruthenium-Catalyzed meta-Selective C-H Mono- and Difluoromethylation of Arenes through ortho-Metalation Strategy. Li ZY, Li L, Li QL, Jing K, Xu H, Wang GW. Chemistry 23 3285-3290 (2017)
  7. Prediction and modeling of effects on the QTc interval for clinical safety margin assessment, based on single-ascending-dose study data with AZD3839. Sparve E, Quartino AL, Lüttgen M, Tunblad K, Gårdlund AT, Fälting J, Alexander R, Kågström J, Sjödin L, Bulgak A, Al-Saffar A, Bridgland-Taylor M, Pollard C, Swedberg MD, Vik T, Paulsson B. J Pharmacol Exp Ther 350 469-478 (2014)
  8. Conformational restriction approach to β-secretase (BACE1) inhibitors III: effective investigation of the binding mode by combinational use of X-ray analysis, isothermal titration calorimetry and theoretical calculations. Yonezawa S, Fujiwara K, Yamamoto T, Hattori K, Yamakawa H, Muto C, Hosono M, Tanaka Y, Nakano T, Takemoto H, Arisawa M, Shuto S. Bioorg Med Chem 21 6506-6522 (2013)
  9. 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)
  10. The Organocatalytic Approach to Enantiopure 2H- and 3H-Pyrroles: Inhibitors of the Hedgehog Signaling Pathway. Kötzner L, Leutzsch M, Sievers S, Patil S, Waldmann H, Zheng Y, Thiel W, List B. Angew Chem Int Ed Engl 55 7693-7697 (2016)
  11. 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)
  12. Fragment-Based Drug Discovery by NMR. Where Are the Successes and Where can It Be Improved? Mureddu LG, Vuister GW. Front Mol Biosci 9 834453 (2022)
  13. Identification of new BACE1 inhibitors using Pharmacophore and Molecular dynamics simulations approach. Dhanabalan AK, Kesherwani M, Velmurugan D, Gunasekaran K. J Mol Graph Model 76 56-69 (2017)
  14. Creation of Novel Cores for β-Secretase (BACE-1) Inhibitors: A Multiparameter Lead Generation Strategy. Viklund J, Kolmodin K, Nordvall G, Swahn BM, Svensson M, Gravenfors Y, Rahm F. ACS Med Chem Lett 5 440-445 (2014)
  15. 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)
  16. Development of 2-aminooxazoline 3-azaxanthene β-amyloid cleaving enzyme (BACE) inhibitors with improved selectivity against Cathepsin D. Low JD, Bartberger MD, Chen K, Cheng Y, Fielden MR, Gore V, Hickman D, Liu Q, Allen Sickmier E, Vargas HM, Werner J, White RD, Whittington DA, Wood S, Minatti AE. Medchemcomm 8 1196-1206 (2017)
  17. Enantioselective Access to 1H-Isoindoles with Quaternary Stereogenic Centers by Palladium(0)-Catalyzed C-H Functionalization. Grosheva D, Cramer N, Cramer N. Angew Chem Int Ed Engl 57 13644-13647 (2018)
  18. Interaction mechanism exploration of HEA derivatives as BACE1 inhibitors by in silico analysis. Wu Q, Li X, Gao Q, Wang J, Li Y, Yang L. Mol Biosyst 12 1151-1165 (2016)
  19. Design, synthesis, and biological evaluation of 4-aminopyrimidine or 4,6-diaminopyrimidine derivatives as beta amyloid cleaving enzyme-1 inhibitors. Xu X, Lü P, Wang J, Xu F, Liang L, Wang C, Niu Y, Xu P. Chem Biol Drug Des 93 926-933 (2019)
  20. Intramolecular N-H⋅⋅⋅F Hydrogen Bonding Interaction in a Series of 4-Anilino-5-Fluoroquinazolines: Experimental and Theoretical Characterization of Electronic and Conformational Effects. Urner LM, Young Lee G, Treacy JW, Turlik A, Khan SI, Houk KN, Jung ME. Chemistry 28 e202103135 (2022)
  21. New substituted aminopyrimidine derivatives as BACE1 inhibitors: in silico design, synthesis and biological assays. Gutiérrez LJ, Parravicini O, Sánchez E, Rodríguez R, Cobo J, Enriz RD. J Biomol Struct Dyn 37 229-246 (2019)
  22. Synthesis and Biological Evaluation of Coumarin Triazoles as Dual Inhibitors of Cholinesterases and β-Secretase. Sharma A, Bharate SB. ACS Omega 8 11161-11176 (2023)


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