Acyl guanidine inhibitors of β-secretase (bACE-1): Optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis

Journal of Medicinal Chemistry

Volumn 55, Issue 21, 2012, Pages 9208-9223

  Gerritz, Samuel W ^a   Zhai, Weixu ^a   Shi, Shuhao ^a   Zhu, Shirong ^a   Toyn, Jeremy H ^a   Meredith, Jere E ^a   Iben, Lawrence G ^a   Burton, Catherine R ^a   Albright, Charles F ^a   Good, Andrew C ^a   Tebben, Andrew J ^a   Muckelbauer, Jodi K ^a   Camac, Daniel M ^a   Metzler, William ^a   Cook, Lynda S ^a   Padmanabha, Ramesh ^a   Lentz, Kimberley A ^a   Sofia, Michael J ^a   Poss, Michael A ^a   MacOr, John E ^a   Thompson, Lorin A ^a   more..

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN[1-42]; BETA SECRETASE 1; BETA SECRETASE INHIBITOR; GUANIDINE DERIVATIVE; N [AMINO [4 [2 (AZETIDIN 1 YL)ACETAMIDO] 3 CHLORO 5 METHYLBENZYLAMINO]METHYLENE] 3 (4 METHOXYPHENYL) 5 METHYLISOTHIAZOLE 4 CARBOXAMIDE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DRUG DISTRIBUTION; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HYDROGEN BOND; NONHUMAN; RAT; REACTION ANALYSIS; SOLID PHASE SYNTHESIS; STRUCTURE ANALYSIS;

AMYLOID BETA-PEPTIDES; AMYLOID BETA-PROTEIN PRECURSOR; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; ASPARTIC ACID ENDOPEPTIDASES; BRAIN; CELL LINE; CRYSTALLOGRAPHY, X-RAY; GUANIDINES; HUMANS; ISOXAZOLES; MODELS, MOLECULAR; MOLECULAR STRUCTURE; MUTATION; PEPTIDE FRAGMENTS; PROTEIN BINDING; RADIOLIGAND ASSAY; RATS; SMALL MOLECULE LIBRARIES; SOLID-PHASE SYNTHESIS TECHNIQUES; SOLUTIONS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84868570563     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm300931y     Document Type: Article

References (32)

1. Querfurth, H. W.; LaFerla, F. M. Alzheimers disease N. Engl. J. Med. 2010, 362, 329-344
2. World Alzheimer Report 2011; Alzheimers Disease International; http://www.alz.co.uk (accessed June 28, 2012).
3. Walsh, D. M.; Selkoe, D. J. Ab oligomers-a decade of discovery J. Neurochem. 2007, 101, 1172-1184
4. Citron, M. Alzheimers disease: strategies for disease modification Nature Rev. Drug Discovery 2010, 9, 387-398
5. McConlogue, L.; Buttini, M.; Anderson, J. P.; Brigham, E. F.; Chen, K. S.; Freedman, S. B.; Games, D.; Johnson-Wood, K.; Lee, M.; Zeller, M.; Liu, W.; Motter, R.; Sinha, S. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP Transgenic Mice J. Biol. Chem. 2007, 282, 26326-26334
6. Ghosh, A. K.; Shin, D.; Downs, D.; Koelsch, G.; Lin, X.; Ermolieff, J.; Tang, J. Design of Potent Inhibitors for Human Brain Memapsin 2 (beta-Secretase) J. Am. Chem. Soc. 2000, 122, 3522-3523
7. Iben, L. G.; Kopcho, L.; Marcinkeviciene, J.; Zheng, C.; Thompson, L. A.; Albright, C. F.; Toyn, J. H. [3H]BMS-599240-a novel tritiated ligand for the characterization of BACE1 inhibitors Eur. J. Pharmacol. 2008, 593, 10-15
8. Kuntz, I. D.; Chen, K.; Sharp, K. A.; Kollman, P. A. The maximal affinity of ligands Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 9997-10002
9. Hopkins, A. L.; Groom, C. R.; Alex, A. Ligand efficiency: a useful metric for lead selection Drug Discovery Today 2004, 9, 430-431
10. Dodd, D. S.; Zhao, Y. Solid-phase synthesis of N, N ′-substituted acylguanidines Tetrahedron Lett. 2001, 42, 1259-1262
11. Wang, S. S. p -Alkoxybenzyl alcohol resin and p - alkoxybenzyloxycarbonylhydrazide resin for solid phase synthesis of protected peptide fragments J. Am. Chem. Soc. 1973, 95, 1328-1333
12. McGregor, D. N.; Corbin, U.; Swigor, J. E.; Cheney, L. C. Synthesis of isothiazoles: the transformation of isoxazoles into isothiazoles Tetrahedron 1969, 25, 389-395
13. Thompson, L. A.; Shi, J.; Decicco, C. P.; Tebben, A. J.; Olson, R. E.; Boy, K. M.; Guernon, J. M.; Good, A. C.; Liauw, A.; Zheng, C.; Copeland, R. A.; Combs, A. P.; Trainor, G. L.; Camac, D. M.; Muckelbauer, J. K.; Lentz, K. A.; Grace, J. E.; Burton, C. R.; Toyn, J. H.; Barten, D. M.; Marcinkeviciene, J.; Meredith, J. E.; Albright, C. F.; Macor, J. E. Synthesis and in vivo evaluation of cyclic diaminopropane BACE-1 inhibitors Bioorg. Med. Chem. Lett. 2011, 21, 6909-6915
14. Marcin, L. R.; Higgins, M. A.; Zusi, F. C.; Zhang, Y.; Dee, M. F.; Parker, M. F.; Muckelbauer, J. K.; Camac, D. M.; Morin, P. E.; Ramamurthy, V.; Tebben, A. J.; Lentz, K. A.; Grace, J. E.; Marcinkeviciene, J. A.; Kopcho, L. M.; Burton, C. R.; Barten, D. M.; Toyn, J. H.; Meredith, J. E.; Albright, C. F.; Bronson, J. J.; Macor, J. E.; Thompson, L. A. Synthesis and SAR of indole- and 7-azaindole-1,3-dicarboxamide hydroxyethylamine inhibitors of BACE-1 Bioorg. Med. Chem. Lett. 2011, 21, 537-541
15. Stachel, S. J.; Coburn, C. A.; Steele, T. G.; Crouthamel, M. C.; Pietrak, B. L.; Lai, M. T.; Holloway, M. K.; Munshi, S. K.; Graham, S. L.; Vacca, J. P. Conformationally biased P3 amide replacements of beta-secretase inhibitors Bioorg. Med. Chem. Lett. 2006, 16, 641-644
16. The PyMOL Molecular Graphics System, version 1.3r1; Schrodinger LLC, 2010.
17. Chenguang, Y.; Williams, R. M. An efficient method for the preparation of amidinoureas Tetrahedron Lett. 1996, 37, 1945-1948
18. Meredith, J. E., Jr.; Thompson, L. A.; Toyn, J. H.; Marcin, L.; Barten, D. M.; Marcinkeviciene, J.; Kopcho, L.; Kim, Y.; Lin, A.; Guss, V.; Burton, C.; Iben, L.; Polson, C.; Cantone, J.; Ford, M.; Drexler, D.; Fiedler, T.; Lentz, K. A.; Grace, J. E., Jr.; Kolb, J.; Corsa, J.; Pierdomenico, M.; Jones, K.; Olson, R. E.; Macor, J. E.; Albright, C. F. P-Glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors in mice J. Pharmacol. Exp. Ther. 2008, 326, 502-513
19. Stachel, S. J.; Coburn, C. A.; Rush, D.; Jones, K. L.; Zhu, H.; Rajapakse, H.; Graham, S. L.; Simon, A.; Katharine Holloway, M.; Allison, T. J.; Munshi, S. K.; Espeseth, A. S.; Zuck, P.; Colussi, D.; Wolfe, A.; Pietrak, B. L.; Lai, M. T.; Vacca, J. P. Discovery of aminoheterocycles as a novel beta-secretase inhibitor class: pH dependence on binding activity part 1 Bioorg. Med. Chem. Lett. 2009, 19, 2977-2980
20. Stachel, S. J.; Steele, T. G.; Petrocchi, A.; Haugabook, S. J.; McGaughey, G.; Katharine Holloway, M.; Allison, T.; Munshi, S.; Zuck, P.; Colussi, D.; Tugasheva, K.; Wolfe, A.; Graham, S. L.; Vacca, J. P. Discovery of pyrrolidine-based beta-secretase inhibitors: lead advancement through conformational design for maintenance of ligand binding efficiency Bioorg. Med. Chem. Lett. 2012, 22, 240-244
21. Weaver, C. D.; Harden, D.; Dworetzky, S. I.; Robertson, B.; Knox, R. J. A thallium-sensitive, fluorescence-based assay for detecting and characterizing potassium channel modulators in mammalian cells J. Biomol. Screening 2004, 9, 671-677
22. Fox, E.; Bates, S. E. Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor Expert Rev. Anticancer Ther. 2007, 7, 447-459
23. Cole, D. C.; Bursavich, M. G. Nonpeptide BACE1 Inhibitors: Design and Synthesis. In Aspartic Acid Proteases as Therapeutic Targets; Wiley-VCH Verlag GmbH & Co. KGaA: New York, 2010; pp 481-509.
24. Zhu, Z.; Sun, Z. Y.; Ye, Y.; Voigt, J.; Strickland, C.; Smith, E. M.; Cumming, J.; Wang, L.; Wong, J.; Wang, Y. S.; Wyss, D. F.; Chen, X.; Kuvelkar, R.; Kennedy, M. E.; Favreau, L.; Parker, E.; McKittrick, B. A.; Stamford, A.; Czarniecki, M.; Greenlee, W.; Hunter, J. C. Discovery of cyclic acylguanidines as highly potent and selective beta-site amyloid cleaving enzyme (BACE) inhibitors: Part I-inhibitor design and validation J. Med. Chem. 2010, 53, 951-965
25. Cole, D. C.; Manas, E. S.; Stock, J. R.; Condon, J. S.; Jennings, L. D.; Aulabaugh, A.; Chopra, R.; Cowling, R.; Ellingboe, J. W.; Fan, K. Y.; Harrison, B. L.; Hu, Y.; Jacobsen, S.; Jin, G.; Lin, L.; Lovering, F. E.; Malamas, M. S.; Stahl, M. L.; Strand, J.; Sukhdeo, M. N.; Svenson, K.; Turner, M. J.; Wagner, E.; Wu, J.; Zhou, P.; Bard, J. Acylguanidines as small-molecule beta-secretase inhibitors J. Med. Chem. 2006, 49, 6158-6161
26. Fobare, W. F.; Solvibile, W. R.; Robichaud, A. J.; Malamas, M. S.; Manas, E.; Turner, J.; Hu, Y.; Wagner, E.; Chopra, R.; Cowling, R.; Jin, G.; Bard, J. Thiophene substituted acylguanidines as BACE1 inhibitors Bioorg. Med. Chem. Lett. 2007, 17, 5353-5356
27. Cole, D. C.; Stock, J. R.; Chopra, R.; Cowling, R.; Ellingboe, J. W.; Fan, K. Y.; Harrison, B. L.; Hu, Y.; Jacobsen, S.; Jennings, L. D.; Jin, G.; Lohse, P. A.; Malamas, M. S.; Manas, E. S.; Moore, W. J.; ODonnell, M. M.; Olland, A. M.; Robichaud, A. J.; Svenson, K.; Wu, J.; Wagner, E.; Bard, J. Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets Bioorg. Med. Chem. Lett. 2008, 18, 1063-1066
28. Malamas, M. S.; Barnes, K.; Johnson, M.; Hui, Y.; Zhou, P.; Turner, J.; Hu, Y.; Wagner, E.; Fan, K.; Chopra, R.; Olland, A.; Bard, J.; Pangalos, M.; Reinhart, P.; Robichaud, A. J. Di-substituted pyridinyl aminohydantoins as potent and highly selective human beta-secretase (BACE1) inhibitors Bioorg. Med. Chem. 2010, 18, 630-639
29. Malamas, M. S.; Erdei, J.; Gunawan, I.; Turner, J.; Hu, Y.; Wagner, E.; Fan, K.; Chopra, R.; Olland, A.; Bard, J.; Jacobsen, S.; Magolda, R. L.; Pangalos, M.; Robichaud, A. J. Design and synthesis of 5,5′-disubstituted aminohydantoins as potent and selective human beta-secretase (BACE1) inhibitors J. Med. Chem. 2010, 53, 1146-1158
30. Malamas, M. S.; Erdei, J.; Gunawan, I.; Barnes, K.; Johnson, M.; Hui, Y.; Turner, J.; Hu, Y.; Wagner, E.; Fan, K.; Olland, A.; Bard, J.; Robichaud, A. J. Aminoimidazoles as potent and selective human beta-secretase (BACE1) inhibitors J. Med. Chem. 2009, 52, 6314-6323
31. Baxter, E. W.; Conway, K. A.; Kennis, L.; Bischoff, F.; Mercken, M. H.; Winter, H. L.; Reynolds, C. H.; Tounge, B. A.; Luo, C.; Scott, M. K.; Huang, Y.; Braeken, M.; Pieters, S. M.; Berthelot, D. J.; Masure, S.; Bruinzeel, W. D.; Jordan, A. D.; Parker, M. H.; Boyd, R. E.; Qu, J.; Alexander, R. S.; Brenneman, D. E.; Reitz, A. B. 2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead J. Med. Chem. 2007, 50, 4261-4264
32. Barrow, J. C.; Stauffer, S. R.; Rittle, K. E.; Ngo, P. L.; Yang, Z.; Selnick, H. G.; Graham, S. L.; Munshi, S.; McGaughey, G. B.; Holloway, M. K.; Simon, A. J.; Price, E. A.; Sankaranarayanan, S.; Colussi, D.; Tugusheva, K.; Lai, M. T.; Espeseth, A. S.; Xu, M.; Huang, Q.; Wolfe, A.; Pietrak, B.; Zuck, P.; Levorse, D. A.; Hazuda, D.; Vacca, J. P. Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of beta-secretase J. Med. Chem. 2008, 51, 6259-6262