Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and Efficacious γ-Secretase Inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.02.039

Discovery of a series of pyrazolopiperidine sulfonamide based γ-secretase inhibitors and its SAR evolution is described. Significant increases in APP potency on the pyrazolopiperidine scaffold over the original N-bicyclic sulfonamide scaffold were achieved and this potency increase translated in an improved in vivo efficacy.

Full text of DOI:10.1016/j.bmcl.2010.02.039

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2195–2199
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and
Efficacious
c-Secretase Inhibitors
a
a
a
a
a
Xiaocong M. Ye a, , Andrei W. Konradi , Jenifer Smith , Ying-Zi Xu , Darren Dressen , Albert W. Garofalo ,
Jennifer Marugg a, Hing L. Sham a, Anh P. Truong a, Jacek Jagodzinski b, Michael Pleiss a, Hongbin Zhang c,
Erich Goldbach c, John-Michael Sauer c, Elizabeth Brigham d, Michael Bova e, Guriqbal S. Basi e
*
a Department of Medicinal Chemistry, Élan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States
b Department of Process and Analytical Chemistry, Élan Pharmaceuticals, 1000 Gateway Boulevard, South San Francisco, CA 94080, United States
c Department of Lead, Discovery, and Optimization, Élan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States
d Department of In Vivo Pharmacology, Élan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States
e Department of Biology, Élan Pharmaceuticals, 1000 Gateway Boulevard, South San Francisco, CA 94080, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Discovery of a series of pyrazolopiperidine sulfonamide based c-secretase inhibitors and its SAR evolu-
Received 17 December 2009
Revised 5 February 2010
Accepted 8 February 2010
Available online 13 February 2010
tion is described. Significant increases in APP potency on the pyrazolopiperidine scaffold over the original
N-bicyclic sulfonamide scaffold were achieved and this potency increase translated in an improved
in vivo efficacy.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Alzheimer’s disease
Amyloid precursor protein
c
c
-Secretase
-Secretase inhibitor
Alzheimer’s disease (AD) is a progressive neurodegenerative
Albright5 and Garofalo6). Herein, we report our progress to discov-
ery potent, selective and orally active, small molecule GSIs.
As reported in another Letter from Mattson et al.,7 a novel series
of potent and selective GSIs exemplified by 1 has been identified in
our laboratories (Fig. 1).
Compound 1 demonstrated good potency and selectivity (15-
fold selectivity over Notch in an enzymatic assay and 90-fold in a
cellular assay) and was efficacious in a wild type FVB mouse model
at 30 mg/kg PO. This series, however, suffers from metabolic insta-
bility. Further limitations include a challenging synthesis that does
not allow for rapid analog development and relatively flat SAR.
Therefore, we initiated efforts to derive a new series aimed at over-
coming the aforementioned limitations.
disorder accompanied by cognitive impairment, memory deficit,
and visual–spatial disorientation. Amyloid plaques and neurofibril-
lary tangles within the hippocampus and the cerebral cortex,
containing aggregated amyloid beta peptide (Ab) and hyperphos-
phorylated tau protein are the defining diagnostic feature of AD.
Aggregation/deposition of Ab in the brain of AD patients is thought
to contribute to AD pathology.1 Ab is a 40–42 amino acid peptide,
formed by sequential cleavage of amyloid precursor protein (APP)
by two aspartyl proteases, b-secretase (BACE) and
c-secretase,
respectively. In addition to APP,
c-secretase also cleaves a large
number of other type 1 transmembrane proteins including Notch.2
The inhibition of Notch proteolysis has been shown to result in
undesirable side effects observed in the thymus, spleen and intes-
Initial effort on the pyrazole region did not yield any single
tine.3 Accordingly, while an inhibitor of
c
-secretase may serve as a
treatment for AD, nonselective inhibitors may find limited utility.
The first example of a -secretase inhibitor (GSI) that achieved
analog that compared with compound 1 in terms of potency7,
c
in vivo inhibition of brain Ab was the dipeptide, DAPT. This work
was jointly reported by researchers from Elan and Eli Lilly.4 Since
then, several classes of nonpeptidic, orally bioavailable GSIs have
been reported in the literature (for recent reviews, see Olson and
O
O
IC50 (APP) = 2 nM
IC50 (Notch) = 29 nM
F = 2.6%
S
Cl
N
N
t
1/2 = 24 min (rat)
N
H
1
* Corresponding author. Tel.: +1 650 616 2683; fax: +1 650 794 2387.
E-mail address: michael.ye@elan.com (X.M. Ye).
Figure 1. Representative N-bicyclic sulfonamide c-secretase inhibitor.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.02.039

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X. M. Ye et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2195–2199
suggesting that the unsubstituted pyrazole is critical for activity.
Analoging efforts in this series clearly demonstrated the need to
maintain the arylsulfonamide. The importance of this pharmaco-
phore to GSIs is further confirmed by its prevalence in a number
of recently patented chemical series.8–16 Therefore, we turned
our attention to the backside hydrocarbon area. Our plan was to
break up the bicyclic skeleton and replace those hydrocarbon
atoms with suitable functional groups in the hope of gaining better
inhibitor potency. Prior to the introduction of pyrazole in our
inhibitors we found 2-alkyl piperidine sulfonamides to be low
micromolar inhibitors (Scheme 1).
Cl
O
S
O
S
O
N
Cl
O
N
NH
N
N
NH
5 IC50 = 4 nM
(racemic mixture of 1)
6
Scheme 2.
Clearly, the substituent scan of the piperidine sulfonamide scaf-
fold revealed that phenyl (4e) was the best for this position (Table
1).17 This result prompted us to initiate a transformation as de-
picted in Scheme 2.
Boc
N
Boc
N
c, d
a, b
The synthesis of compound 6 is illustrated in Scheme 3. Starting
with commercially available ketone 7, a procedure reported by
Trost et al.18 was able to provide us the desired pyrazole 8 with
excellent regiochemistry-control. After deprotection, sulfonylation
occurred on both the piperidine and pyrazole nitrogens. Hydrolysis
of the pyrazole sulfonamide with sodium hydroxide led to the
racemate 6.
N
NH
O
7
8
Cl
O
Cl
S
O
O
N
S
N
e
O
As anticipated, compound 6 was quite potent in our
c APP assay
and markedly more selective over Notch compared with com-
pound 1 (Table 2). Encouraged by this result, further analogs were
prepared as illustrated in Scheme 4. Using a two step procedure re-
ported by Kozikowski and Park,19 the commercially available Cbz
protected 4-piperidinone was converted to enone 11. Comins and
co-workers20 have reported that a copper-catalyzed conjugate
addition by alkyl Grignard reagent worked very well on this enone
system. Following his protocol, we found that it worked as well for
aryl Grignard reagents to lead to compound 12. Standard chemis-
try as described in Scheme 3 was used then to afford compound 15.
Unfortunately, the copper-catalyzed conjugate addition did not
work for heteroaromatic Grignard reagents. Therefore, a Diels-Al-
der strategy22 was employed to make key intermediate 19
(Scheme 5). Formylation of these analogs, however, did not afford
single regioisomers. Instead, inseparable mixtures were obtained
with 2-pyridylpiperidinones after pyrazole formation. 2-Pyrimidi-
nylpiperidinones gave mixtures that were separable using chiral
HPLC. The mixture of four isomers after pyrazole formation and
the active enantiomer from each pair are listed in Table 2.
N
S
N
O
Cl
N
NH
O
6
9
Scheme 3. Reagents and conditions: (a) HCO2Et, NaH, MeOH, PhH; (b) N2H4ÁH2O,
MeOH, rt; (c) TFA, rt; (d) 4-chlorobenzenesulfonyl chloride, pyridine; (e) NaOH,
THF, H2O.
was applied to separate all four isomers. Accordingly, compounds
20e, 21e and 21f–g were synthesized from the corresponding
esters.
As shown in Table 2, although only a slight improvement in po-
tency was achieved while changing halogens and their substitution
pattern on the phenyl ring at the C-6 position, those compounds (6
and 15a–d) demonstrated significantly higher selectivity ratio in
both enzymatic and cellular assays23 over compound 1. Interest-
ingly, when the phenyl group was replaced by benzyl group,
potency decreased 10-fold and selectivity also dropped. When a
Similarly, compounds 20d and 21d were synthesized using
ethyl glyoxylate as the starting aldehyde. Once again, chiral HPLC
R
R
Cbz
N
Cl
Cbz
N
Cbz
N
Cbz
N
O
a, b
Cl
c
d, e
H
N
S
N
R1
R2
O
a
O
R1
R2
S
N
O
NH
O
O
O
Cl
10
12
11
13
2
3
4
Cl
Scheme 1. Reagents: (a) pyridine, O/N.
Cl
O
S
R
O
S
R
O
N
O
f, g
h
Table 1
N
Structure–activity relationships of N-arylsulfonylated piperidine
a
Compound
R1
R2
c
APP IC50 (nM)
Notes
N
S
N
Cl
N
NH
4a
4b
4c
4d
4e
4f
H
Me
Et
n-Pr
Ph
Me
H
H
H
H
H
Me
>30,000
O
O
8278 1964
2002 912
1698 72
760 82
Racemic
Racemic
Racemic
Racemic
cis, rac
15
14
Scheme 4. Reagents and conditions: (a) Br2, ethylene glycol; (b) DBU, DMSO, 85 °C,
then HCl; (c) CuBrÁSMe2, BF3ÁOEt2, THF, Grignard reagent; (d), HCO2Et, NaOH, PhH,
MeOH; (e) N2H4ÁH2O, MeOH, rt; (f) HBr, DCM or Pd/C, H2, MeOH; (g) pyridine, 4-
chlorobenzenesulfonyl chloride; (h) NaOH, THF, H2O.
1004 227
a
Values are means of at least three experiments with standard errors

X. M. Ye et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2195–2199
2197
Table 2
In vitro activities of synthetic analogs of the pyrazolopiperidine series
Cl
Cl
O
O
S
S
N
O
O
R
N
R
4
6
3
HN
1
HN
N
N
2
20
21
a
a
Compound
R
c
(nM)
APP IC50
c
Notch
SNC Cell ED50
(nM)
SNC
IC50 (nM)
c
Notch
Glucuron. microsom.
% remainc
Oxidat. metabol.
% remaind
Notes
a
a
IC50 (nM)
(human)
(human)
6
Ph
4-ClPh
4-FPh
3-FPh
3,5-diFPh
PhCH2
i-Pr
3-Pyridyl
4-Pyridyl
5-Pyrimidyl
5-Pyrimidyl
CO2Et
7.7 0.2
598 41
311 41
481 14
662 54
776 61
1554b
55.3 5.0
17.5b
6514 806
2586b
5319 645
11,397 1467
14,126 1367
16,625 1528
6759 529
14,770b
8
5
12
12
6
14
3
Racemic
Racemic
Racemic
Racemic
Racemic
Racemic
Racemic
rac, regio mix. of 4
rac, regio mix. of 4
Active enant.
Active enant.
Active enant.
Active enant.
Racemic
15a
15b
15c
15d
15e
15f
20/21a
20/21b
20c
21c
20d
21d
20e
21e
21f
3.4 0.2
5.4 0.1
8.3 0.1
9.7 0.3
80.9 2.2
16.1 0.7
96.7 2.4
451 6.2
536 19
12.0 0.6
431 22
10.2 0.1
244 13
29.1 2.7
557 46
350 6.2
33
N/A
0
28.0 4.4
47.1 10
60.1 7.2
340 67
86 12
558b
0
N/A
N/A
57
26
70
85
0
1
8
59
N/A
37
87b
3
1109b
67
21
67
50
8
5431b
1419b
>40,000
>40,000
10,375 943
120 14
5851b
400b
47.1 11
2305 145
>40,000
1423b
CO2Et
204b
137b
10263b
1
2-Thiazolyl
2-Thiazolyl
CH2OH
5750 900
858 122
8658b
1271b
33565b
54
57
84
15
139b
6527b
Racemic
Active enant.
Racemic
3127b
>40,000
>40,000
21g
CH2OC(O)NMe2
8251b
5324b
a
b
c
Values are means of three experiments with standard errors unless noted.
Values are single experiment or means of two experiments.
Percentage of compound (2
lM) remaining after 30 min incubation in liver microsomes (0.5 mg protein) supplemented with 1 mM UDPGA, 100 mM MgCl2 and 25
l
g/mL
alamethacin at 37 °C in phosphate buffer.
d
Percentage of compound (1
lM) remaining after 30 min incubation in liver microsomes (0.5 mg protein) supplemented with 1 mM NADPH at 37 °C in phosphate buffer.
simply alkyl group such as iso-propyl was used at this position
(compound 15f), potency decreased just twofold. Clearly, substitu-
tion at C-4 position achieves a better potency than it at C-6 posi-
tion (compound 21c vs 20c, 21d vs 20d). When the ester group
was converted to the alcohol and carbamate group, substantial loss
in potency was observed. These results suggest the binding pocket
in the right side of the molecule is very sensitive.
While it is clear that aryl group at C-6 position is better than al-
kyl group in terms of potency, we need to discover if this is the case
for C-4 position. This is even more important if we consider that
the SAR at C-4 position seems more sensitive than C-6. From Table
1, an ethyl group is clearly better than methyl group in terms of po-
tency for that simple piperidine sulfonamide. Therefore, we
decided to synthesize a compound with ethyl group at C-4
position.
The synthesis is illustrated in Scheme 6. Reaction of 4-methoxy-
pyridine with benzyl chloroformate followed by Grignard addition
with ethylmagnesium bromide gave the 2,3-dihydropyridinone
23.20 Treatment with DMF–DMA complex afforded the enamine
intermediate, to which was then added hydrazine to form the pyr-
azole 24. Hydrogenation with palladium on carbon as the catalyst
cleaved the Cbz group and reduced the double bond simulta-
neously. Once again, the sulfonylation occurred at both nitrogen
Cbz
Cbz
N
H
N
N
N
f
a, b, c
d, e
O
O
N
N
NH
NH
OMe
O
23
SO2NH2
S
N
a
b
22
24
25
het
het
Cl
CHO Cl
O
Cl
Cl
O
17
16
18
Cl
S
Cl
O
S
O
Cl
h
g
N
O
O
O
N
S
N
S
N
O
O
S
het
het
O
c, d
het
N
HN
S
N
O
Cl
N
NH
O
N
N
HN
NH
26
27
O
19
20
21
Scheme 6. Reagents: (a) CbzCl, PhMe; (b) EtMgBr, THF; (c) HCl; (d) DMF–DMA; (e)
N2H4ÁH2O, HOAc; (f) Pd/C, H2, MeOH; (g) pyridine, 4-chlorobenzenesulfonyl
chloride; (h) NaOH, THF, H2O.
Scheme 5. Reagents: (a) 4A MS, MP-TsOH, PhMe, reflux; (b) Danishefsky diene,
THF, reflux; (c) HCO2Et, NaOEt or DMF–DMA; (d) N2H4ÁH2O.

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X. M. Ye et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2195–2199
atoms. After treatment with NaOH, the desired final product was
obtained.
illustrated in Scheme 7 using similar strategy as scheme 6. It is
noteworthy that the Grignard addition gave predominately syn ad-
duct.21 Formylation led to two regioisomers in a 2:5 ratio, which
were then carried forward separately to the final products 32
and 34.
Surprisingly, the combination resulted in potency loss com-
pared with compound 27, as compound 32 is 20 nM and 34 is
3.3 nM.
The
c APP assay (see Table 3) reveals that compound 27 is not
only more potent than compound 15f (1 nM vs 16 nM), but also
surpasses compound 1. At this point, it seems that the best substi-
tuent at the 6-position is 4-chlorophenyl and ethyl group at the 4-
position. Therefore, we decided to synthesize compound 34 which
combines the best substituents into one molecule. The synthesis is
Table 3
In vitro activities of synthetic analogs of the pyrazolopiperidine series
O
S
R3
O
R2
N
R1
HN
N
Compound
R1
R2
R3
c
APP
c
Notch
SNC Cell
ED50 (nM)
SNC
IC50 (nM)
c
Notch
Glucuron. microsom.
% remainc (human)
Oxidat. metabol.
Notes
% remaind (human)
a
a
a
a
IC50 (nM)
IC50 (nM)
27
32
34
35
36
37
38
Et
Et
4-ClPh
Et
Et
H
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-CF3-Ph
1.01 0.03
3.7 0.4
15.3b
19.0 4.4
16.7b
736 185
1568b
N/A
31
25
2
1
1
18
10
4
1
1
rac, cis
rac, cis
rac, cis
rac, cis
ent. A of 40
ent. B of 40
rac, cis
4-ClPh
Et
Et
Et
Et
75.5b
22.4 1.2
0.48 0.01
0.35 0.03
62.6 5.2
0.77 0.02
125.5b
5.0 0.2
5.8 1.3
N/A
182.3b
1.27b
15455b
123b
0.98 0.2
70
8
Et
c-Pr
157b
6854b
295b
0
10
c-Pr
23.4b
2.8b
32
a
b
c
Values are means of three experiments with standard errors unless noted.
Values are single experiment or means of two experiments.
Percentage of compound (2
l
M) remaining after 30 min incubation in liver microsomes (0.5 mg protein) supplemented with 1 mM UDPGA, 100 mM MgCl2 and 25
lg/mL
alamethacin at 37 °C in phosphate buffer.
d
Percentage of compound (1
lM) remaining after 30 min incubation in liver microsomes (0.5 mg protein) supplemented with 1 mM NADPH at 37 °C in phosphate buffer.
Cl
Cl
Cl
Cbz
N
Cbz
N
Cbz
N
Cbz
N
a
b, c
O
N
N
NH
O
HN
23
28
29
30
(70%)
(30%)
d, e
Cl
Cl
Cl
Cl
O
S
N
O
O
S
O
+
N
Cl
N
S
N
S
N
O
N
Cl
Cl
O
O
O
31
33
f
Cl
Cl
f
O
S
N
O
Cl
O
S
N
O
N
HN
32
N
NH
34
Scheme 7. Reagents and conditions: (a) 4-chlorophenylmagnesium bromide, CuBrÁSMe2, BF3ÁOEt2; (b) NaH, HCO2Et, MeOH, PhH; (c) N2H4ÁH2O; (d) TMSI, CH3CN; (e) 4-
chlorobenzenesulfonyl chloride.

X. M. Ye et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2195–2199
2199
Cl
Cl
Cl
O
S
O
S
O
S
O
O
O
chiral HPLC separation
N
N
N
N
N
NH
NH
N
NH
36
37
35
Scheme 8.
to improve its in vivo pharmacokinetic profile will be reported in
another Letter.
Acknowledgements
We would like to thank Gary D. Probst, Daniel Ness, Lee Latimer,
Michael Dappen, Jing Wu, David Quincy, Pam Keim, Lan Nguyen,
William Wallace, David Nakamura, Karina Wong, Wes Zmolek, Mi-
chael Lee, Kang Hu, Anna Liao, Terence Hui, Tracy Cole, Cristian
Cabrera, Ferdie Soriano, Bhushan Samant, Rose Lawler, Juri Fukada
for their contributions to this work. We also would like to thank
Wherly Hoffman for data statistics analysis and Hu Pan for X-ray
structure display.
Figure 2. Compound 37 (inactive enantiomer).
Although we do not have a clear understanding of this result,
we believe the potency loss may be due to steric effect that forces
the molecule to twist its conformation. We then decided to make
the simple diethyl substituted compound and to see if this less
crowded molecule would be more potent.
References and notes
1. (a) Selkoe, D. J.; Schenk, D. Annu. Rev. Pharmacol. Toxicol. 2003, 43, 545; (b)
Wolfe, M. S. J. Med. Chem. 2001, 44, 2039.
The same chemistry illustrated in Scheme 7 was used to make
this symmetrical di-substituted pyrazolopiperidine compounds
such as 35, just switching the 4-chlorophenylmagnesium bromide
with ethylmagnesium bromide. Indeed, compound 35 is extremely
potent demonstrating picomolar APP activity (see Table 3). Com-
pound 35 was subjected to chiral HPLC separation using Chiralcel
OD column, eluting with ethanol/hexane mixture, to afford both
enantiomers, 36 and 37, each in greater than 99% ee (Scheme 8).
Absolute configuration of the compound 37 (the inactive enantio-
mer) was determined by analysis of anomalous X-ray scattering by
the single crystal. The determination (CCDC 764934) indicates that
the spatial configuration of the active isomer, 36, is analogous to
compound 17 (see Fig. 2).
2. Radtke, F.; Wilson, A.; Mancini, J. C.; MacDonal, H. R. Nat. Immunol. 2004, 5, 247.
3. Wong, G. T.; Manfra, D.; Poulet, F. M.; Zhang, Q.; Josien, H.; Bara, T.; Engstrom,
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Y.; Freedman, S. B.; Folmer, B.; Goldbach, E.; Holsztynska, E. J.; Hu, K. L.;
Johnson-Wood, K. L.; Kennedy, S. L.; Kholodenko, D.; Knops, J. E.; Latimer, L. H.;
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L. N.; Britton, T. C.; Clemens, J. C.; Czilli, D. L.; Dieckman-McGinty, D. K.; Droste,
J. J.; Fuson, K. S.; Gitter, B. D.; Hyslop, P. A.; Johnstone, E. M.; Li, W.-Y.; Little, S.
P.; Mabry, T. E.; Miller, F. D.; Ni, B.; Nissen, J. S.; Porter, W. J.; Potts, B. D.; Reel, J.
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Although compound 36 is extremely potent, it still suffers from
poor metabolic stability. Metabolic identification studies revealed
that the poor metabolic stabilities arise from the ethyl groups
and the methylene group adjacent to pyrazole ring. Also, the stud-
ies revealed that the p-chlorobenzenesulfonamide was oxidized to
an epoxide followed by glutathione conjugation. The glutathione
conjugation problem was alleviated when trifluoromethyl was
used to replace the chlorine substituent. At the same time, the
diethyl groups were replaced by dicyclopropyl groups and the sub-
sequent molecule 38 (its synthesis will be disclosed in a separate
Letter) afforded higher stability in an in vitro glucuronidation as-
say, although it still performed poorly in an in vitro oxidation as-
say. Table 3 lists the data of those compounds.
The in vivo efficacy of compound 36 was evaluated in the wild
type FVB mouse model. A significant 25% Ab40 reduction was ob-
served 3 h after a single 5 mg/kg po dose of 36 (brain/plasma: 0.8).
In summary, we have identified a novel, potent and efficacious
series of c-secretase inhibitors. This series displays in vivo activity
for reduction of brain Ab. Although this series achieved a good effi-
7. Mattson, M. N.; Neitzel, M. L.; Quincy, D. A.; Semko, C. M.; Garofalo, A. W.;
Keim, P. S.; Konradi, A. W.; Pleiss, M. A.; Sham, H. L.; Brigham, E. F.; Goldbach, E.
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cacy result, it has suffered from poor metabolic stability. Our effort