M. Pettersson et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2906–2911
2911
Table 4
MacCoss, M.; Mandal, M. B.; McCracken, T.; Nomeir, A.; Mazzola, R.; Palani, A.;
Parker, E. M.; Pissarnitski, D. A.; Qin, J.; Song, L.; Terracina, G.; Vicarel, M.; Voigt,
J.; Xu, R.; Zhang, L.; Zhang, Q.; Zhao, Z.; Zhu, X.; Zhu, Z. J. Med. Chem. 2012, 55,
489.
Rat pharmacokinetics data. Guinea pig efficacy data at 100 mg/kg po, 4 h post-dose.
CL
T1/2 (h)
Vdss (L)
% F
% Ab4228
% Ab4028
(mL/min/kg)
reduction in
brain (%)
reduction
in brain (%)
10. In general, oral drugs tend to have a LipE between 5 and 7; see: Leeson, P. D.;
Springthorpe, B. Nat. Rev. Drug Disc. 2007, 6, 881.
11. LogD at pH 7.4 calculated using ACD version 9.03.
35
43
9.63
31.4
2.43
0.64
1.87
1.78
100
51 36
57
32
16
12. (a) Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P.
R.; Villalobos, A.; Will, T. ACS Chem. Neurosci. 2010, 1, 420; An analysis of a set
of CNS drugs (N = 119) showed that 74% have a CNS MPO score P4 on a scale of
0–6: see: (b) Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. ACS Chem.
Neurosci. 2010, 1, 435.
13. Hughes, J. D.; Blagg, J.; Price, D. A.; Bailey, S.; DeCrescenzo, G. A.; Devraj, R. V.;
Ellsworth, E.; Fobian, Y. M.; Gibbs, M. E.; Gilles, R. W.; Greene, N.; Huang, E.;
Krieger-Burke, T.; Loesel, J.; Wager, T.; Whiteley, L.; Zhang, Y. Bioorg. Med.
Chem. Lett. 2008, 18, 4872.
polarity could be increased without introducing P-gp efflux liabil-
ity. Current efforts are focused on further improving potency while
maintaining good alignment of pharmacokinetic parameters and
physicochemical properties. These efforts will be described in
due course.
14.
A hydrogen bond acceptor in the form of an amide, lactam, or various
heterocycles in this region of the molecule is present in the majority of non-
NSAID GSMs throughout the patent literature (see Ref. 6a,b).
15. Pfizer, Inc. WO10100606, 2010.
16. Pfizer, Inc. WO11048525, 2011.
Acknowledgments
17. Novartis AG, WO 11130379, 2011.
18. Sreedhar, B.; Venkanna, G. T.; Kumar, K. B. S.; Balasubrahmanyam, V. Synthesis
2008, 5, 795.
We would like to thank Stacey Becker, Emily Miller, Michael
Marconi, Donald Tyszkiewicz, Emily Sylvain, and Karin Wallace
for their contributions to the in vivo studies. We would also like
to thank Dr. Patrick R. Verhoest for helpful suggestions in prepar-
ing this article.
19. Eisai R&D Management Co., Ltd. US090062529, 2009.
20. Stepan, A. F.; Karki, K.; McDonald, W. S.; Dorff, P. H.; Dutra, J. K.; DiRico, K. J.;
Won, A.; Subramanyam, C.; Efremov, I. V.; O’Donnell, C. J.; Nolan, C. E.; Becker,
S. L.; Pustilnik, L. R.; Sneed, B.; Sun, H.; Lu, Y.; Robshaw, A. E.; Riddell, D.;
O’Sullivan, T. J.; Sibley, E.; Capetta, S.; Atchison, K.; Hallgren, A. J.; Miller, E.;
Wood, A.; Obach, R. S. J. Med. Chem. 2011, 54, 7772.
References and notes
21. Assay method adapted from published protocols: (a) Riley, R. J.; McGinnity, D.
F.; Austin, R. P. Drug Metab. Dispos. 2005, 33, 1304; (b) Obach, R. S. Drug Metab.
Dispos. 1999, 27, 1350.
22. Feng, B.; Mills, J. B.; Davidson, R. E.; Mireles, R. J.; Janiszewski, J. S.; Troutman,
M. D.; de Morais, S. M. Drug Metab. Dispos. 2008, 36, 268.
23. A compound with a MDR efflux ratio (MDR Er) less than 2.5 is considered to
have minimal P-gp efflux liability.
program clogP, version 4.3.
25. TorreyPines Therapeutics, Inc.WO08137102, 2008. The compound from this
patent application that inspired the synthesis of 33 is shown below:
1. Wimo, A.; Prince, M. World Alzheimer Report 2010: The Global Economic Impact
of Dementia; Alzheimer’s Disease International (ADI): London, U.K., 2010.
2. Walsh, D. M.; Selkoe, D. J. J. Neurochem. 2007, 101, 1172.
3. De Strooper, B.; Vassar, R.; Golde, T. Nat. Rev. Neurol. 2010, 6, 99.
4. Haapasalo, A.; Kovacs, D. M. J. Alzheimers Dis. 2011, 25, 3.
5. (a) Saxena, U. Expert Opin. Ther. Targets 2010, 14, 273; (b) Imbimbo, B. P.; Panza,
F.; Frisardi, V.; Solfrizzi, V.; D’Onofrio, G.; Logroscino, G.; Seripa, D.; Pilotto, A.
Expert. Opin. Investig. Drugs 2011, 20, 325; (c) Xia, X.; Qian, S.; Soriano, S.; Wu,
Y.; Fletcher, A. M.; Wang, X. J.; Koo, E. H.; Wu, X.; Zheng, H. Proc. Natl. Acad. Sci.
U.S.A. 2001, 98, 10863; (d) Schor, N. F. Ann. Neurol. 2011, 69, 237.
6. (a) Pettersson, M.; Kauffman, G. W.; am Ende, C. W.; Patel, N. C.; Stiff, C.; Tran,
T. P.; Johnson, D. S. Expert Opin. Ther. Pat. 2011, 21, 205; (b) Oehlrich, D.;
Berthelot, D. J.-C.; Gijsen, H. J. M. J. Med. Chem. 2011, 54, 669; (c) Zettl, H.;
Weggen, S.; Schneider, P.; Schneider, G. Trends Pharmacol. Sci. 2010, 31, 402.
7. (a) Crump, C. J.; Fish, B. A.; Castro, S. V.; Chau, D.-M.; Gertsik, N.; Ahn, K.; Stiff,
C.; Pozdnyakov, N.; Bales, K. R.; Johnson, D. S.; Li, Y.-M. ACS Chem. Neurosci.
2011, 69, 705; (b) Ohki, Y.; Higo, T.; Uemura, K.; Shimada, N.; Osawa, S.;
Berezovska, O.; Yokoshima, S.; Fukuyama, T.; Tomita, T.; Iwatsubo, T. EMBO J.
2011, 30, 4815; (c) Ebke, A.; Luebbers, T.; Fukumori, A.; Shirotani, K.; Haass, C.;
Baumann, K.; Steiner, H. J. Biol. Chem. 2011, 286, 37181; (d) Crump, C. J.;
Johnson, D. S.; Li, Y.-M. EMBO J. 2011, 30, 4696.
O
H
N
N
O
N
N
O
26. For the original report concerning the dihydrobenzofuranol synthesis see: (a)
Holt, B.; Lowe, P. A. Tetrahedron Lett. 1966, 7, 683; For the Corey–Chaykovsky
reagent see: (b) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867; (c)
Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
8. Portelius, E.; Van Broeck, B.; Andreasson, U.; Gustavsson, M. K.; Mercken, M.;
Zetterberg, H.; Borghys, H.; Blennow, K. J. Alzheimers Dis. 2010, 1005, 21.
9. For other strategies to replace the cinnamide moiety see: (a) Lubbers, T.; Flohr,
A.; Jolidon, S.; David-Pierson, P.; Jacobsen, H.; Ozmen, L.; Baumann, K. Bioorg.
Med. Chem. Lett. 2011, 21, 6554; (b) Qin, J.; Dhondi, P.; Huang, X.; Mandal, M.;
Zhao, Z.; Pissarnitski, D.; Zhou, W.; Aslanian, R.; Zhu, Z.; Greenlee, W.; Clader, J.;
Zhang, L.; Cohen-Williams, M.; Jones, N.; Hyde, L.; Palani, A. Bioorg. Med. Chem.
Lett. 2011, 21, 664; (c) Caldwell, J. P.; Bennett, C. E.; McCracken, T. M.; Mazzola,
R. D.; Bara, T.; Buevich, A.; Burnett, D. A.; Chu, I.; Cohen-Williams, M.; Josein,
H.; Hyde, L.; Lee, J.; McKittrick, B.; Song, L.; Terracina, G.; Voigt, J.; Zhang, L.;
Zhu, Z. Bioorg. Med. Chem. Lett. 2010, 20, 5380; (d) Huang, X.; Aslanian, R.; Zhou,
W.; Zhu, X.; Qin, J.; Greenlee, W.; Zhu, Z.; Zhang, L.; Hyde, L.; Chu, I.; Cohen-
Williams, M.; Palani, A. ACS Med. Chem. Lett. 2010, 1, 184; (e) Qin, J.; Zhou, W.;
Huang, X.; Dhondi, P.; Palani, A.; Aslanian, R.; Zhu, Z.; Greenlee, W.; Cohen-
Williams, M.; Jones, N.; Hyde, L.; Zhang, L. ACS Med. Chem. Lett. 2011, 2, 471; (f)
Sun, Z.-Y.; Asberom, T.; Bara, T.; Bennett, C.; Burnett, D.; Chu, I.; Clader, J.;
Cohen-Williams, M.; Cole, D.; Czarniecki, M.; Durkin, J.; Gallo, G.; Greenlee, W.;
Josien, H.; Huang, X.; Hyde, L.; Jones, N.; Kazakevich, I.; Li, H.; Liu, X.; Lee, J.;
27. Single enantiomers were obtained by chiral separation of amines 30 or
following the final amide coupling.
28. Male Hartley guinea pigs, weighing 200–250 g were administered vehicle or
GSM 35 or 43 100 mg/kg orally. Brain, CSF and plasma were sampled at 4 h
post-dose. Brains were homogenized in 0.4%DEA/50 mM NaCl, incubated
overnight at 4 °C, then centrifuged at 135,000g for 1 h. Supernatant was
collected for analysis. Plasma was incubated overnight with 5 M GuHCl. The
DELFIA method was used to measure total Ab1-x, Abx-42, Abx-40 and Ab1-38
in brain supernatant, CSF and Plasma. CSF was diluted directly in assay buffer.
Brain extracts and GuHCl-plasma were run over solid-phase extraction to
remove nonspecific signal and concentrate.
29. Drug exposure data for compound 35 (mean SD, n = 5): total plasma
concentration = 5120 2396 ng/mL,
plasma
Fu = 0.088;
total
brain
concentration = 22140 6826 ng/g, brain Fu = 0.018. Drug exposure data for
compound 43 (mean SD, n = 5): total plasma concentration = 1288 892 ng/
mL, plasma Fu = 0.078; total brain concentration = 3708 2309 ng/g, brain
Fu = 0.0097.