M. Teall et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2685–2688
Table 4. c-Secretase inhibition for cyclic sulfons 15, 21–24
2687
O
O
S
R1
R3
R2
Entry
R1
R2
R3
IC50 (nM)5
15
21
22
23
24
F
F
H
H
F
F
H
F
H
F
Cl
Cl
Cl
Cl
H
3
55
249
461
98
clearly depicted the 2,5-difluoroaryl group in the axial
position (Fig. 1).14
To investigate the importance of the halogen substitu-
ents, a series of sulfones 21–24 were prepared (Table
4) following the general procedures outlined in Schemes
1 and 2.
Scheme 3. Reagents and conditions: (i) RuCl3, NaIO4, CHCl3–H2O,
rt, 70%; (ii) LiAlH4, THF, 65%; (iii) MeSO2Cl, Et3N, CH2Cl2, 0 ꢁC,
92%; (iv) KOtBu, NaH, THF, 5, 28%.
A decrease in potency was observed with removal of the
5-fluoro (21), the 2-fluoro substituent (22) or both (23).
Removal of the 4-chloro substituent in the aryl sulfone
ring, as in analogue (24) also resulted in a decrease in
potency (IC50 98 nM). All substituents are therefore
contributing to the high potency of the c-secretase inhibi-
tor 15.
experiments12. In analogue 19 the ortho-fluorophenyl
proton was shown to be in close proximity to the C-2
equatorial proton of the cyclohexane and the proton
on the ethylene bridge. For analogue 20 NOEÕs were ob-
served from the ortho-fluorophenyl proton to both the 2-
axial and 2-equatorial protons and the ortho-chlorophen-
yl proton also showed an NOE to the proton on the
ethylene bridge, indicating that the SO2Ar group exists
in the axial orientation (Scheme 3). In analogue 15
NOEÕs were observed between the ortho-fluorophenyl
proton and the 2-equatorial and 3-axial protons on the
cyclohexane. Taken together, these experiments suggest
that the more potent bicyclic analogues (19 IC50 12 nM)
and 15 (IC50 3 nM) possess the 2,5-difluoroaryl group in
the axial position. This suggestion is supported by the
work of Eliel and Manoharan13 who showed that the
larger phenyl group in 1-methyl-1-phenylcyclohexane
prefers to exist in the energetically favourable axial posi-
tion. An X-ray structure was obtained compound 15
In conclusion, we have described a series of novel, aryl
sulfone c-secretase inhibitors, which possesses a simple
pharmacophore, and requires only a three step synthesis
to prepare potent compounds (e.g., 15, IC50 3 nM). The
contribution of the halogen aromatic substituents was
investigated, with the 2,5-difluorophenyl and 4-chloro-
phenyl groups found to be essential to maintain high
potency. Finally, using NMR experiments, analogy with
structurally defined analogues (19 and 20), and an X-ray
it was concluded that the 2,5-difluoroaryl group resides
in the axial position in the active conformer of 15.
Acknowledgements
We thank Jonathan Wrigley, Dirk Beher, Earl Clarke
and Huw Lewis for their support in obtaining the data.
References and notes
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Invest. Drugs 2001, 10, 593; Conde, S. Exp. Opin. Ther.
Patents 2002, 12, 503; Dominguez, D. I.; De Strooper, B.;
Annaert, W. Amyloid 2001, 8, 124.
2. Gong, Y.; Chang, L.; Viola, K. L.; Lacor, P. N.; Lambert,
M. P.; Finch, C. E.; Krafft, G. A.; Klein, W. L. Proc. Natl.
Acad. Sci. U.S.A. 2003, 100, 10417.
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4790; Selkoe, D. J. Trends Cell Biol. 1998, 8, 447; Bayer, T.
Figure 1. X-ray crystal structure of compound 15.