Journal of Medicinal Chemistry
Article
(35) Auberson, Y.; Glatthar, R.; Salter, R.; Simic, O.; Tintelnot-
Blomley, M. Preparation of substituted spirocyclic lactams as inhibitors
of proteinase BACE1. Patent WO2005035535, 2005.
imidazolidinone BACE-1 inhibitors. Bioorg. Med. Chem. Lett. 2008,
18, 3236−3241. (i) Chirapu, S. R.; Pachaiyappan, B.; Nural, H. F.;
Cheng, X.; Yuan, H.; Lankin, D. C.; Abdul-Hay, S. O.; Thatcher, G. R.;
Shen, Y.; Kozikowski, A. P.; Petukhov, P. A. Molecular modeling,
synthesis, and activity studies of novel biaryl and fused-ring BACE1
inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 264−274. (j) Charrier,
N.; Clarke, B.; Cutler, L.; Demont, E.; Dingwall, C.; Dunsdon, R.;
Hawkins, J.; Howes, C.; Hubbard, J.; Hussain, I.; Maile, G.; Matico, R.;
Mosley, J.; Naylor, A.; O'Brien, A.; Redshaw, S.; Rowland, P.; Soleil,
V.; Smith, K. J.; Sweitzer, S.; Theobald, P.; Vesey, D.; Walter, D. S.;
Wayne, G. Second generation of BACE-1 inhibitors. Part 1: The need
for improved pharmacokinetics. Bioorg. Med. Chem. Lett. 2009, 19,
3664−3668. (k) Charrier, N.; Clarke, B.; Demont, E.; Dingwall, C.;
Dunsdon, R.; Hawkins, J.; Hubbard, J.; Hussain, I.; Maile, G.; Matico,
R.; Mosley, J.; Naylor, A.; O'Brien, A.; Redshaw, S.; Rowland, P.;
Soleil, V.; Smith, K. J.; Sweitzer, S.; Theobald, P.; Vesey, D.; Walter, D.
S.; Wayne, G. Second generation of BACE-1 inhibitors part 2:
Optimisation of the non-prime side substituent. Bioorg. Med. Chem.
Lett. 2009, 19, 3669−3673. (l) Charrier, N.; Clarke, B.; Cutler, L.;
Demont, E.; Dingwall, C.; Dunsdon, R.; Hawkins, J.; Howes, C;
Hubbard, J.; Hussain, I.; Maile, G.; Matico, R.; Mosley, J.; Naylor, A.;
O'Brien, A.; Redshaw, S.; Rowland, P.; Soleil, V.; Smith, K. J.; Sweitzer,
S.; Theobald, P.; Vesey, D.; Walter, D. S.; Wayne, G. Second
generation of BACE-1 inhibitors part 3: Towards non-hydroxyethyl-
amine transition state mimetics. Bioorg. Med. Chem. Lett. 2009, 19,
3674−3678. (m) Sealy, J. M.; Truong, A. P.; Tso, L.; Probst, G. D.;
Aquino, J.; Hom, R. K.; Jagodzinska, B. M.; Dressen, D.; Wone, D. W.;
Brogley, L.; John, V.; Tung, J. S.; Pleiss, M. A.; Tucker, J. A.; Konradi,
(36) (a) Seelig, A.; Landwojtowicz, E. Structure-activity relationship
of P-glycoprotein substrates and modifiers. Eur. J. Pharm. Sci. 2000, 12,
31−40. (b) Seelig, A. A general pattern for substrate recognition by P-
glycoprotein. Eur. J. Biochem. 1998, 251, 252−261. (c) Cianchetta, G.;
Singleton, R. W.; Zhang, M.; Wildgoose, M.; Giesing, D.; Fravolini, A.;
Cruciani, G.; Vaz, R. J. A pharmacophore hypothesis for P-
glycoprotein substrate recognition using GRIND-based 3D-QSAR. J.
Med. Chem. 2005, 48, 2927−2935. (d) Didziapetris, R.; Japertas, P.;
Avdeef, A.; Petrauskas, A. Classification analysis of P-glycoprotein
substrate specificity. J. Drug Target 2003, 11, 391−406.
(37) For recent reviews discussing hydroxyethylamine (HEA) and
nontransition state isostere-based inhibitors of BACE1, see (a) Silvestri,
R. Boom in the development of non-peptidic beta-secretase (BACE1)
inhibitors for the treatment of Alzheimer's disease. Med. Res. Rev. 2009,
29, 295−338. (b) Hamada, Y.; Kiso, Y. Recent progress in the drug
discovery of non-peptidic BACE1 inhibitors. Expert Opin. Drug
Discovery 2009, 4, 391−416. (c) Stachel, S. J. Progress toward the
development of a viable BACE-1 inhibitor. Drug Dev. Res. 2009, 70,
101−110.
(38) For recent papers discussing HEA BACE1 inhibitors, see
(a) Maillard, M. C.; Hom, R. K.; Benson, T. E.; Moon, J. B.; Mamo, S.;
Bienkowski, M.; Tomasselli, A. G.; Woods, D. D.; Prince, D. B.;
Paddock, D. J.; Emmons, T. L.; Tucker, J. A.; Dappen, M. S.; Brogley,
L.; Thorsett, E. D.; Jewett, N.; Sinha, S.; John, V. Design, synthesis,
and crystal structure of hydroxyethyl secondary amine-based
peptidomimetic inhibitors of human beta-secretase. J. Med. Chem.
2007, 50, 776−781. (b) Charrier, N.; Clarke, B.; Cutler, L.; Demont,
E.; Dingwall, C.; Dunsdon, R.; East, P.; Hawkins, J.; Howes, C.;
Hussain, I.; Jeffrey, P.; Maile, G.; Matico, R.; Mosley, J.; Naylor, A.;
O'Brien, A.; Redshaw, S.; Rowland, P.; Soleil, V.; Smith, K. J.; Sweitzer,
S.; Theobald, P.; Vesey, D.; Walter, D. S.; Wayne, G. Second
generation of hydroxyethylamine BACE-1 inhibitors: Optimizing
potency and oral bioavailability. J. Med. Chem. 2008, 51, 3313−3317.
(c) Iserloh, U.; Wu, Y.; Cumming, J. N.; Pan, J.; Wang, L. Y.;
Stamford, A. W.; Kennedy, M. E.; Kuvelkar, R.; Chen, X.; Parker, E.
M.; Strickland, C.; Voigt, J. Potent pyrrolidine- and piperidine-based
BACE-1 inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 414−417.
(d) Iserloh, U.; Pan, J.; Stamford, A. W.; Kennedy, M. E.; Zhang, Q.;
Zhang, L.; Parker, E. M.; McHugh, N. A.; Favreau, L.; Strickland, C.;
Voigt, J. Discovery of an orally efficacious 4-phenoxypyrrolidine-based
BACE-1 inhibitor. Bioorg. Med. Chem. Lett. 2008, 18, 418−422.
(e) Clarke, B.; Demont, E.; Dingwall, C.; Dunsdon, R.; Faller, A.;
Hawkins, J.; Hussain, I.; MacPherson, D.; Maile, G.; Matico, R.;
Milner, P.; Mosley, J.; Naylor, A.; O’Brien, A.; Redshaw, S.; Riddell,
D.; Rowland, P.; Soleil, V.; Smith, K. J.; Stanway, S.; Stemp, G.;
Sweitzer, S.; Theobald, P.; Vesey, D.; Walter, D. S.; Ward, J.; Wayne,
G. BACE-1 inhibitors part 2: Identification of hydroxy ethylamines
(HEAs) with reduced peptidic character. Bioorg. Med. Chem. Lett.
2008, 18, 1017−1021. (f) Beswick, P.; Charrier, N.; Clarke, B.;
Demont, E.; Dingwall, C.; Dunsdon, R.; Faller, A.; Gleave, R.;
Hawkins, J.; Hussain, I.; Johnson, C. N.; MacPherson, D.; Maile, G.;
Matico, R.; Milner, P.; Mosley, J.; Naylor, A.; O'Brien, A.; Redshaw, S.;
Riddell, D.; Rowland, P.; Skidmore, J.; Soleil, V.; Smith, K. J.; Stanway,
S.; Stemp, G.; Stuart, A.; Sweitzer, S.; Theobald, P.; Vesey, D.; Walter,
D. S.; Ward, J.; Wayne, G. BACE-1 inhibitors part 3: Identification of
hydroxy ethylamines (HEAs) with nanomolar potency in cells. Bioorg.
Med. Chem. Lett. 2008, 18, 1022−1026. (g) Park, H.; Min, K.; Kwak,
H.-S.; Koo, K. D.; Lim, D.; Seo, S.-W.; Choi, J.-U.; Platt, B.; Choi, D.-
Y. Synthesis, SAR, and X-ray structure of human BACE-1 inhibitors
with cyclic urea derivatives. Bioorg. Med. Chem. Lett. 2008, 18, 2900−
2904. (h) Cumming, J. N.; Le, T. X.; Babu, S.; Carroll, C.; Chen, X.;
Favreau, L.; Gaspari, P.; Guo, T.; Hobbs, D. W.; Huang, Y.; Iserloh,
U.; Kennedy, M. E.; Kuvelkar, R.; Li, G.; Lowrie, J.; McHugh, N. A.;
Ozgur, L.; Pan, J.; Parker, E. M.; Saionz, K.; Stamford, A. W.;
Strickland, C.; Tadesse, D.; Voigt, J.; Wang, L.; Wu, Y.; Zhang, L.;
Zhang, Q. Rational design of novel, potent piperazinone and
́
A. W.; Dappen, M. S.; Toth, G.; Pan, H.; Ruslim, L.; Miller, J.; Bova,
M. P.; Sinha, S.; Quinn, K. P.; Sauer, J.-M. Design and synthesis of cell
potent BACE-1 inhibitors: structure-activity relationship of P1′
substituents. Bioorg. Med. Chem. Lett. 2009, 19, 6386−6391.
(n) Truong, A. P.; Probst, G. D.; Aquino, J.; Fang, L.; Brogley, L.;
Sealy, J. M.; Hom, R. K.; Tucker, J. A.; John, V.; Tung, J. S.; Pleiss, M.
́
A.; Konradi, A. W.; Sham, H. L.; Dappen, M. S.; Toth, G.; Yao, N.;
Brecht, E.; Pan, H.; Artis, D. R.; Ruslim, L.; Bova, M. P.; Sinha, S.;
Yednock, T. A.; Zmolek, W.; Quinn, K. P.; Sauer, J. M. Improving the
permeability of the hydroxyethylamine BACE-1 inhibitors: Structure-
activity relationship of P2′ substituents. Bioorg. Med. Chem. Lett. 2010,
20, 4789−4794. (o) Probst, G. D.; Bowers, S.; Sealy, J. M.; Stupi, B.;
Dressen, D.; Jagodzinska, B. M.; Aquino, J.; Gailunas, A.; Truong, A.
P.; Tso, L.; Xu, Y.-Z.; Hom, R. K.; John, V.; Tung, J. S.; Pleiss, M. A.;
Tucker, J. A.; Konradi, A. W.; Sham, H. L.; Jagodzinski, J.; Toth, G.;
Brecht, E.; Yao, N.; Pan, H.; Lin, M.; Artis, D. R.; Ruslim, L.; Bova, M.
P.; Sinha, S.; Yednock, T. A.; Gauby, S.; Zmolek, W.; Quinn, K. P.;
Sauer, J.-M. Design and synthesis of hydroxyethylamine (HEA)
BACE-1 inhibitors: structure-activity relationship of the aryl region.
Bioorg. Med. Chem. Lett. 2010, 20, 6034−6039. (p) Truong, A. P.;
Toth, G.; Probst, G. D.; Sealy, J. M.; Bowers, S.; Wone, D. W.;
́
Dressen, D.; Hom, R. K.; Konradi, A. W.; Sham, H. L.; Wu, J.;
Peterson, B. T.; Ruslim, L.; Bova, M. P.; Kholodenko, D.; Motter, R.
N.; Bard, F.; Santiago, P.; Ni, H.; Chian, D.; Soriano, F.; Cole, T.;
Brigham, E. F.; Wong, K.; Zmolek, W.; Goldbach, E.; Samant, B.;
Chen, L.; Zhang, H.; Nakamura, D. F.; Quinn, K. P.; Yednock, T. A.;
Sauer, J.-M. Design of an orally efficacious hydroxyethylamine (HEA)
BACE-1 inhibitor in a preclinical animal model. Bioorg. Med. Chem.
Lett. 2010, 20, 6231−6236. (q) 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. (r) Boy, K. M.; Guernon, J. M.;
Shi, J.; Toyn, J. H.; Meredith, J. E.; Barten, D. M.; Burton, C. R.;
Albright, C. F.; Marcinkeviciene, J.; Good, A. C.; Tebben, A. J.;
Muckelbauer, J. K.; Camac, D. M.; Lentz, K. A.; Bronson, J. J.; Olson,
R. E.; Macor, J. E.; Thompson, L. A. III. Monosubstituted γ-lactam
and conformationally constrained 1,3-diaminopropan-2-ol transition-
3384
dx.doi.org/10.1021/jm300069y | J. Med. Chem. 2012, 55, 3364−3386