Discovery of sulfonamide-pyrazole γ-secretase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.02.050

Utilizing a pharmacophore hypothesis, previously described γ-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide-pyrazoles, with high in vitro potency, good brain penetration, low metabolic stability, and high clearance.

Full text of DOI:10.1016/j.bmcl.2010.02.050

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2148–2150
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of sulfonamide–pyrazole c-secretase inhibitors
Matthew N. Mattson, Martin L. Neitzel, David A. Quincy, Christopher M. Semko, Albert W. Garofalo,
*
Pamela S. Keim, Andrei W. Konradi , Michael A. Pleiss, Hing L. Sham, Elizabeth F. Brigham,
Erich G. Goldbach, Hongbin Zhang, John-Michael Sauer, Guriqbal S. Basi
Elan Pharmaceuticals, 800 Gateway Blvd., 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:
Utilizing a pharmacophore hypothesis, previously described c-secretase inhibiting HTS hits were evolved
into novel tricyclic sulfonamide–pyrazoles, with high in vitro potency, good brain penetration, low met-
abolic stability, and high clearance.
Received 16 December 2009
Revised 10 February 2010
Accepted 10 February 2010
Available online 14 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Alzheimer’s disease
c
-secretase inhibitor
Sulfonamide
Alzheimer’s disease (AD) is the foremost cause of dementia
low energy conformations, preventing the definition of a specific
three-dimensional pharmacophore, but the symmetry of 4 permit-
ted empirical exploration of hydrogen-bond donors in many posi-
tions relative to the essential 4-chlorobenzenesulfonamide.
Initially, we converted nor-pseudopelletierine5 (5) into a group
of hydrazones, alcohols, and amines, as illustrated in Scheme 1.6
None of the compounds in Scheme 1 have potencies superior to
4, and therefore we redirected our efforts to fusing 4 with protic
heterocycles, as illustrated in Scheme 2. Quite remarkably, the very
among elderly persons worldwide.1 Amyloid plaques containing
aggregated Ab peptide, and neurofibrillary tangles containing hy-
per-phosphorylated tau protein, within the hippocampus and the
cerebral cortex, are the diagnostic pathologies of AD. Ab peptide
is a 40–42 aminoacid peptide, formed by sequential cleavage of
Amyloid precursor protein (APP) by the proteases b-secretase
(BACE) and
brain has not been proven to cause AD, inhibitors of BACE and
secretase are the subject of much drug discovery research. Several
c-secretase. Although deposition of Ab peptide in the
c
-
c
-secretase inhibitors (GSIs) are in clinical trials, as are agents tar-
geting Ab peptide by different mechanisms.2 This Letter describes
the discovery of a new class of GSIs.
High throughput screening (HTS) of circa 500 K small molecules
revealed 1 to be a moderately potent GSI (Fig. 1 and Table 1).3,4 Hit
expansion based on 1 provided many compounds with comparable
or increased potencies, including 2a and 3. Two aspects of SAR
were clear following hit expansion. First, the 4-chlorobenzenesulf-
onamide is nearly optimal for potency. Second, the N–H caprolac-
tam 2a is much more potent than its N-methyl analog 2b. We
hypothesized the N–H group in 2a may donate a hydrogen bond
to c-secretase. Modeling of 3 revealed a global minimum, in which
the piperidine ring is a slightly flattened chair, and the methyl
groups and the arylsulfonyl group all are nearly axial. This confor-
mation suggested preparing the bicycle 4, which proved to be as
potent as 3. We hypothesized, adding a hydrogen-bond donor to
4 might increase its potency. Modeling of 2a revealed multiple
* Corresponding author. Tel.: +1 650 794 4393.
E-mail address: andrei.konradi@elan.com (A.W. Konradi).
Figure 1. Screening hits and hit expansion compounds.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.02.050

M. N. Mattson et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2148–2150
2149
Table 1
Inhibition of c-secretase by compounds not N–H pyrazoles
Compound
IC50 (nM)
1
650
2a
25
2b
3
1700
1700
4
1300
7a
3300
7b
7c
7d
8a
>10,000
>10,000
8000
3000
8b
9a
600
>10,000
>10,000
>10,000
>10,000
3500
>10,000
>10,000
4700
9b
11b
11c
12
14
16a
16b
16c
16d
16e
9000
>10,000
5500
Scheme 2. Ar = 4-ClC6H4. All compounds meso or racemic. Reagents: (a) EtO2CH,
NaH, THF; (b) H2NNH2 or HONH2, EtOH; (c) MeI, NaH, DMF; (d) C5H5NHBr3,
toluene; (e) SC(NH2)2, THF; (f) neat SOCl2; (g) R1C(@NH)NH2, EtOH, to 16a, 16c, 16e;
(h) Raney Ni, EtOH; (i) BBr3, CH2Cl2.
Scheme 1. Ar = 4-ClC6H4. All compounds meso or racemic. Reagents: (a) ArSO2Cl,
pyridine; (b) R1NH2, EtOH; (c) NaBH4, EtOH; (d) PhCO2H, PPh3, EtO2CN@NCO2Et,
THF; (e) NaOH, THF/H2O; (f) NH4OAc, NaBH3CN, MeOH, and then separation of
diastereomers by HPLC.
first fused heterocycle we prepared, the pyrazole 11a, proved to be
500-fold more potent than 4. The high potency of 11a suggested
we explore other heterocycles in the place of the pyrazole. Interest-
ingly, the N-methyl pyrazoles 11b–c, the isoxazole 12, the 2-ami-
nothiazole 14, and several pyrimidines 16a–e are not more
potent than 4.
Next, we prepared a group of substituted N–H pyrazoles, as
illustrated in Schemes 3 and 4. The in vitro potencies of several
substituted N–H pyrazoles are indicated in Table 2. Substituents
larger than H on the un-fused carbon atom within the pyrazole
diminish potency (11a vs 11d–j). Oxygen or fluorine substituents
on the CH2 adjacent to the pyrazole have minor effects on potency
(11a vs 11k–l). The very high potency of 11a, relative to the other
heteroaromatics in Scheme 2, suggests the N–H pyrazole in 11a
Scheme 3. Ar = 4-ClC6H4. All compounds meso or racemic. Reagents: (a) R1CO2Et,
NaH, THF; (b) N2H4, EtOH; (c) KOtBu, CS2, MeI, THF; (d) C5H5NHBr3, toluene; (e)
KCN, THF/H2O; (f) formalin, NaBH3CN, AcOH, MeOH; (g) neat Ac2O.
may form two hydrogen bonds with
c-secretase, similar to the
known interaction of some N–H pyrazoles with backbone carbox-
amides in the ATP-binding sites of kinases.7
We separated the enantiomers of 11a by chiral HPLC, and we
determined only the positively rotating enantiomer is more potent
than 4. X-ray crystallography showed (+)-11a has the configuration
illustrated in Scheme 2, and the solid-state conformation illus-
Scheme 4. Ar = 4-ClC6H4. All compounds meso or racemic. Reagents: (a) CrO3, HIO4,
AcOH; (b) neat F3SN(CH2CH2OMe)2.

2150
M. N. Mattson et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2148–2150
trated in Figure 2.8 X-ray crystallography showed 2a has the solid-
state conformation illustrated in Figure 3.8 In the solid-state
conformations of (+)-11a and 2a, the respective pyrazole and
carboxamide occupy similar positions relative to the 4-chloroben-
zenesulfonamide, consistent with these groups hydrogen-bonding
In Sprague-Dawley rats, (+)-11a exhibits low oral availability
(F = 2%) and high clearance (CL = 2200 mL/kg/h). However, 3 h after
a 100 mg/kg oral dose in FVB mice, (+)-11a achieves a 194 nM con-
centration in plasma, an 86 nM concentration in cortex, and a 36%
reduction of Abx-40 in cortex.9 Experiments utilizing rat and hu-
man liver microsomes revealed (+)-11a suffers efficient metabolic
oxidation and glucuronidation, the latter generating isomers from
glucuronyl transfer to either pyrazole nitrogen atom in the unoxi-
dized parent molecule.4 Given the high in vitro potency and excel-
lent brain penetration of (+)-11a, several related series of
sulfonamide–pyrazole GSIs have been investigated, in pursuit of
compounds with superior metabolic stability.10
to c-secretase.
Table 2
Inhibition of
c
-secretase by N–H pyrazoles
Acknowledgements
Compound
R1
R2
IC50 (nM)
Michael Lee, Hu Kang, Susanna Hemphill, Terence Hui, Kevin
Tanaka, Lan Nguyen, Jill Labbe, Jim Miller, Nancy Jewett, Michael
Bova, Russel Cacavello, Jennifer Marugg, Jing Wu, Michael Dappen,
Lee Latimer, John Maynard, Christine Olivero, Ronald Morgan,
Brian Peterson, Ferdinand Soriano, Danielle Pappas, Jon
Hawkinson.
11a
11d
11e
11f
11g
11h
11i
11j
11k
11l
H,H
H,H
H,H
H,H
H,H
H,H
H,H
H,H
O
H
Me
4
65
70
85
390
105
>10,000
70
8
3
CF3
CHF2
SMe
NH2
NMe2
NHAc
H
References and notes
F,F
H
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Figure 2. X-ray crystal structure of (+)-11a.
8. (À)-11a CCDC 764936; 2a CCDC 764935.
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Figure 3. X-ray crystal structure of 2a.