1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as selective glucocorticoid receptor antagonists with high functional activity

Article abstract of DOI:10.1016/j.bmcl.2008.01.027

Addition of the 4-fluorophenylpyrazole group to the previously described 2-azadecalin glucocorticoid receptor (GR) antagonist 1 resulted in significantly enhanced functional activity. SAR of the bridgehead substituent indicated that whereas groups as small as methyl afforded high GR binding, GR functional activity was enhanced by larger groups such as benzyl, substituted ethers, and aminoalkyl derivatives. GR antagonists with binding and functional activity comparable to mifepristone were discovered (e.g., 52: GR binding K_i 0.7 nM; GR reporter gene functional K_i 0.6 nM) and found to be highly selective over other steroid receptors. Analogues 43 and 45 had >50% oral bioavailability in the dog.

Full text of DOI:10.1016/j.bmcl.2008.01.027

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 1312–1317
1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as selective
glucocorticoid receptor antagonists with high functional activity
Robin D. Clark,a,* Nicholas C. Ray,b Karen Williams,b Paul Blaney,b Stuart Ward,b
Peter H. Crackett,b Christopher Hurley,b Hazel J. Dyke,b David E. Clark,b
Peter Lockey,b Rene Devos,b Melanie Wong,b Soraya S. Porres,b Colin P. Bright,b
Robert E. Jenkinsb and Joseph Belanoffa
aCorcept Therapeutics, 149 Commonwealth Avenue, Menlo Park, CA 94025, USA
bArgenta Discovery, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom
Received 18 November 2007; revised 4 January 2008; accepted 8 January 2008
Available online 11 January 2008
Abstract—Addition of the 4-fluorophenylpyrazole group to the previously described 2-azadecalin glucocorticoid receptor (GR)
antagonist 1 resulted in significantly enhanced functional activity. SAR of the bridgehead substituent indicated that whereas groups
as small as methyl afforded high GR binding, GR functional activity was enhanced by larger groups such as benzyl, substituted
ethers, and aminoalkyl derivatives. GR antagonists with binding and functional activity comparable to mifepristone were discovered
(e.g., 52: GR binding Ki 0.7 nM; GR reporter gene functional Ki 0.6 nM) and found to be highly selective over other steroid recep-
tors. Analogues 43 and 45 had >50% oral bioavailability in the dog.
Ó 2008 Elsevier Ltd. All rights reserved.
Although potential therapeutic indications for glucocor-
ticoid receptor (GR) antagonists have been identified,1
Y
O
O
O
O
S
S
the need for selective agents remains. Recent progress
toward this goal has been reviewed.1 The standard GR
antagonist mifepristone (RU-486)3 is a potent progester-
one receptor (PR) antagonist which places significant re-
straints on its clinical utility. Our interest in the
development of a follow-on compound to mifepristone
for the treatment of psychotic major depression
(PMD)4 led to our discovery of selective GR antagonists
exemplified by the 2-azadecalinone 1 which have high
affinity for GR and modest GR functional antagonist
activity.2 These compounds are structurally related to
the steroid RU-43044, which is selective for GR but
lacks oral bioavailability.3b,c Herein we report that fu-
sion of the phenylpyrazolo group to the azadecalin ring
system (Fig. 1) leads to GR antagonists with signifi-
cantly increased functional activity and somewhat diver-
gent SAR from the previous series. The introduction of
the pyrazolo ring onto the azadecalin scaffold was based
N
N
N
N
O
z
1
F
Figure 1. From enone series to fused pyrazoles.
on the presence of this structural feature in the potent
GR agonist fluorocortivazol.5 Others have utilized this
strategy for the preparation of selective GR partial ago-
nists based on the decalin ring system.6
Formylation of homochiral enone 12 followed by reac-
tion with 4-fluorophenylhydrazine furnished the 1H-
pyrazolo[3,4-g]hexahydroisoquinoline
3 (Scheme 1).
The regiochemistry of formylation and arylpyrazole
formation is consistent with that observed in steroidal
A-ring enone systems5 and hexahydro-2(3H)-naphthale-
nones.6,7 Benzyl-protected amine 5 was similarly pre-
pared in racemic form from enone 4.2 N-debenzylation
of 5 followed by derivatization afforded compounds
( )-6–21 (Scheme 2 and Table 1).
Keywords: Glucocorticoid receptor (GR) antagonist; Pyrazolo-fused
azadecalins.
*
Corresponding author. Tel./fax: +1 808 332 5449; e-mail addresses:
rclark@corcept.com; robin.clark5@hawaiiantel.net
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.01.027

R. D. Clark et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1312–1317
1313
Analogues containing an angular methyl substituent
were prepared as shown in Scheme 3. The (3R)-piperi-
done 238a was prepared by chiral imine mediated Mi-
chael addition as previously described.8 The benzyl
group was switched to Boc by hydrogenolysis and treat-
ment with di-tert-butyl dicarbonate to facilitate N-
deprotection later in the synthetic sequence. Cyclization
of the resulting Boc-protected diketone 24 gave enone
25. Formylation of 25 was accomplished by conversion
to the enolate with LDA followed by reaction with
2,2,2-trifluoroethyl formate,9 a sequence that was more
convenient and higher yielding than the traditional
NaH/ethyl formate procedure used in Schemes 1 and
2. As previously noted for Wieland–Miescher ketone
derivatives,6a the regiochemistry of the two formylation
procedures is the same. Sulfonamides 27–34 (Table 2)
were subsequently prepared in standard fashion from
aryl pyrazole 26.
Me
N
Me
Me
OH
OH
O
O
RU-43044
Mifepristone
O
OAc
OH
HO
N
N
Fluorocortivazol
F
Bridgehead ether derivatives 41–57 were prepared com-
mencing from the known homochiral enone 3510 by the
reaction sequence shown in Scheme 4. Intermediate
alcohols 38–40 were also converted to amine analogues
61–79 via reductive amination of the aldehydes 58–60
(Scheme 5).11
O
O
O
O
S
S
N
HO
N
a
O
O
1
2
O
O
S
Ligand binding was used to determine GR affinity by
measurement of [3H]dexamethasone displacement from
recombinant baculovirus derived human GR.12 Func-
tional GR antagonist activity was measured as inhibi-
tion of dexamethasone induced luciferase expression in
SW1353/MMTV-5 cells transfected with a plasmid
encoding firefly luciferase located behind a glucocorti-
coid response element (GRE).12 GR agonist activity
N
b
N
N
3
F
Scheme 1. Reagents and conditions: (a) HCO2Et, NaH, toluene; (b) 4-
fluorophenylhydrazine hydrochloride, AcOH, NaOAc, rt.
F
F
F
Bn
Bn
X
a,b
c,d
N
N
N
N
N
N
N
O
5
4
6-21
F
F
Scheme 2. Reagents and conditions: (a) HCO2Et, NaH, toluene; (b) 4-fluorophenyl hydrazine hydrochloride, AcOH, NaOAc, rt; (c)
ClCO2CHClCH3, dichloroethane, reflux; MeOH, reflux; (d) 6–15: sulfonyl chloride, NEt3, CH2Cl2; 16: phenylboronic acid, Cu(OAc)2, Et3N,
CH2Cl2; 17–20: benzyl bromide or 2,3, or 4-picolyl bromide, NaH, THF; 21: benzoyl chloride, Et3N, CH2Cl2.
Bn
N
Bn
BOC
a,b
c
d
N
O
N
O
N
O
O
N
O
22
23
24
X
BOC
BOC
N
N
g,h
e,f
N
N
N
O
25
26
27-34
F
F
Scheme 3. Reagents and conditions: (a) (R)-a-methylbenzylamine, toluene, reflux; (b) methylvinyl ketone, THF, 50 °C; (c) H2, Pd/C, EtOH, BOC2O;
(d) NaOMe, MeOH; (e) LDA, Et2O, À78 °C; HCO2CH2CF3; (f) 4-fluorophenyl hydrazine hydrochloride, AcOH, NaOAc, rt; (g) 20% TFA/CH2Cl2;
(h) RSO2Cl, diisopropylethylamine, CH2Cl2.

1314
R. D. Clark et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1312–1317
MeO
O
MeO
O
O
MeO
O
O
BOC
c,d
BOC
S
N
a,b
N
N
N
N
N
N
O
Z
36
37
35
F
F
HO
RO
O
O
O
O
S
S
f
N
N
e
N
N
N
N
Z
Z
41-57
38-40
F
F
Scheme 4. Reagents and conditions: (a) LDA, Et2O, À78 °C; HCO2CH2CF3; (b) 4-fluorophenyl hydrazine hydrochloride, AcOH, NaOAc, rt; (c)
20% TFA/CH2Cl2; (d) ArSO2Cl, diisopropylethylamine, CH2Cl2; (e) DIBAL-H, CH2Cl2, À78 °C to rt; (f) NaH, THF, RBr or RI, rt-reflux.
R1R2N
N
O
O
O
O
O
S
S
a
N
b
N
N
38-40
N
N
Z
Z
58-60
61-79
F
F
Scheme 5. Reagents and conditions: (a) DMSO, COCl2, TEA, À45 °C; (b) R1R2NH, NaBH(OAc)3, dichloroethane.
could be measured in the same assay in the absence of
dexamethasone. Standard ligand binding assays were
used to measure selectivity over other steroid receptors
(ER, AR, MR, and PR).13
Table 1. GR binding affinity and functional activity for 3, 6–21a
F
O
O
S
X
N
N
N
N
N
N
6-21
F
3
F
Compound
X
GR Binding Ki (nM)b
GR Functional Ki (nM)b
3
1.4
1.3
2.2
1.5
1.4
1.3
13
4.7
14
6
S(O2)-4-(t-butyl)-phenyl
S(O2)-phenyl
7
36
17
8
S(O2)-4-Me-phenyl
S(O2)-4-F-phenyl
9
10
26
11
S(O2)-4-(morpholin-4-yl)-phenyl
S(O2)Me
S(O2)-n-butyl
11
12
>1000
>1000
343
12
13
14
S(O2)-2-(t-butyl)-pyrid-5-yl
S(O2)-morpholin-4-yl
S(O2)-NH-phenyl
Phenyl
4.5
26
>1000
68
438
15
16
3
15
17
18
Benzyl
2.5
18
245
390
CH2-pyrid-2-yl
CH2-pyrid-3-yl
CH2-pyrid-4-yl
C(O)-phenyl
19
20
22
41
>1000
>1000
21
1
Mifepristone
>1000
4
0.4
200
1.2
a Compounds 6–21 are racemic.
b Values are means of two experiments.

R. D. Clark et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1312–1317
Table 2. GR binding affinity and functional activity for 27–34, 38–57, and 61–79a
1315
Y
O
O
O
O
S
S
N
N
N
N
N
N
Z
Z
27-34
38-57, 61-79
F
F
Compound
Y
Z
GR Binding Ki (nM)b
GR Functional Ki (nM)b
27
28
29
30
31
32
33
34
2-Me
4-Me
4-t-Bu
2-F
22
2.3
1.2
34
9
nt
96
53
nt
4-F
293
178
78
4-OMe
4-CF3
4-NH2
3.7
3.4
17
>1000
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
OH
OH
H
10
nt
47
4-t-Bu
4-F
1.6
8.6
1.0
0.5
1.4
0.8
0.8
0.8
0.9
0.9
0.5
0.3
0.6
0.7
0.8
0.8
0.8
12
OH
OCH3
184
20
H
OCH3
OCH3
4-Me
4-F
5.7
33
OCH3
OCH3
4-t-Bu
4-CF3
4-t-Bu
4-CF3
4-CF3
H
7.7
28
OCH2CH3
OCH2CH3
OCH2CH2CH3
OCH2CH2OMe
OCH2CH2OMe
OCH2CH2OMe
OCH2CH2OMe
OCH2CH2OH
1.9
6.8
9.0
2.9
1.2
5.2
0.6
8.7
1.6
5.1
201
77
4-Me
4-F
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
OCH2CH2CH2OMe
OCH2CH2CN
OCH2CH2(pyrrolidin-1-yl)
OCH2CH2(piperidin-1-yl)
8.6
61
62
NHEt
NH-i-Pr
4-t-Bu
4-t-Bu
4-t-Bu
H
2.4
2.1
0.9
1.1
2.6
1.2
1.7
2.8
1.0
3.8
1.4
1.5
1.6
1.1
0.8
1.6
0.6
0.9
6.7
0.4
16
17
63
64
NH-allyl
NMe2
11
10
65
66
NMe2
NMe2
NEt2
4-F
29
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
H
6.9
14
67
68
NHCH2CH2OH
NHCH2CH2OMe
NHCH2CH2NMe2
Azetidin-1-yl
Pyrrolidin-1-yl
Pyrrolidin-1-yl
Pyrrolidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Morpholin-1-yl
Morpholin-1-yl
4-Methylpiperazin-1-yl
28
69
70
3.1
60
71
72
11
4.9
8.0
3.4
5.8
5.8
18
73
74
4-F
4-t-Bu
H
75
76
4-t-Bu
H
77
78
4-t-Bu
4-tBu
7.1
85
79
Mifepristone
1.2
a All compounds have the absolute stereochemistry indicated.
b Values are means of two experiments.
cnt, not tested.
Fusion of the aryl pyrazole group onto enone 1 led to a
ca. 40-fold increase in GR functional activity as com-
pound 3 was found to have Ki of 4.7 nM compared to
200 nM for 12 (Table 1). The enantiospecificity of GR
binding (and functional activity) of the enone series
was conserved as the racemate corresponding to 3 was

1316
R. D. Clark et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1312–1317
Table 3. Pharmacokinetic data for selected compounds
Compound
Species
Dose (mg/kg po)a
Cmax (ng/mL)
AUC (lg/h/mL)
t1/2 (h)
F (%)
Brain/plasma ratio
29
41
43
44
45
78
29
41
43
45
Rat
Rat
Rat
Rat
Rat
Rat
Dog
Dog
Dog
Dog
5
199
23
1.009
0.112
0.621
0.430
0.966
0.302
1.684
0.894
1.676
3.638
2.7
3.6
2.1
2.9
3.4
2.0
4.2
5.9
4.2
6.7
13
3
0.07
0.75
1.1
5
5
106
94
22
11
16
10
26
20
54
58
5
0.10
0.83
0.10
—
5
163
75
5
2.5
2.5
2.5
2.5
524
258
381
647
—
—
—
a Compounds were administered in 10% DMSO/90% methylcellulose (1% water). N = 3 for rat studies and N = 2 for dog studies.
of lower activity (binding Ki = 3.6 nM, functional Ki
30 = nM). N-substituents were surveyed for the related
p-fluorophenyl derivatives 6–21 (tested as racemates).
The SAR diverged from that of the enone series2 as
other substituents, notably N-benzyl, provided high
binding affinity (compound 17); however, N-sulfonyl
derivatives continued to demonstrate superior func-
tional GR antagonist activity. Whereas aryl sulfona-
mides again showed the best antagonist profile, the
penchant for the p-tert-butyl group in the enone series
was diminished as evidenced by the functional activity
of 7–10.
noted (Table 1), differences in GR functional activity
emerged among compounds with similar binding
affinity.
Ethers were significantly more active than the alcohol
progenitors as GR functional antagonists (e.g. compare
alcohol 39 with ethers 44, 52–55). For direct compara-
tors (i.e., compounds containing the same benzenesul-
fonamide) there was a trend toward increased GR
functional activity with increasing size of the ether
group, although the trend was not completely linear
(44 vs 46, 52, 54; 45 vs 47, 48). Derivatives with an ami-
noalkyl group at the bridgehead also showed high GR
functional activity with the exception of those that con-
tained more distal polar functionality (68, 70, 79). The
same phenomenon was noted in the ether series where
terminal amine-substituted ethyl ethers 56 and 57
showed significantly lower GR functional activity. A
similarity between the ether and amine series was that
compounds with the highest functional activity con-
tained the methoxyethyl group (52: Ki = 0.6 nM and
69: Ki = 3.1 nM).
Having made a rather significant structural change from
enone 1 to aryl pyrazole 3, it was of interest to re-exam-
ine the structural requirements of the bridgehead substi-
tuent. In the enone series, the bridgehead benzyl group
was an apparent key to high GR binding affinity, at least
in comparison to the angular methyl compound which
was essentially devoid of affinity.14 During the course
of this work, GR partial agonist activity was reported
for bridgehead methyl substituted arylpyrazole deriva-
tives in the decalin series.6 We were thus prompted to
prepare compounds 27–34 (Table 2). The direct compar-
ators 3 (Table 1) and 29 indicated that the bridgehead
benzyl group was not required for GR binding; how-
ever, the antagonist activity was enhanced in the benzyl
derivative (4.7 nM for 3 vs. 53 nM for 29). Notably,
bridgehead methyl derivative 29 was devoid of GR
agonist activity in the functional assay (as was com-
pound 3).
The high selectivity for GR of the enone series2 was re-
tained in the 4-fluorophenylpyrazoles as none of the
analogues in Tables 1 and 2 displaced 50% binding at
ER, AR, MR or PR at 10 lM. Many of these com-
pounds are in the same range as mifepristone in GR
functional potency and represent a significant advance
given the lack of selectivity of the latter over PR (mife-
pristone PR binding = 1.3 nM).
The high GR affinity and modest functional antagonist
activity of 29 prompted synthesis of other bridgehead
derivatives as a means to provide increased polarity
and possibly lower molecular weight relative to the
highly lipophilic benzyl compound 3 (MW = 555,
cLogP = 8.5). Bridgehead alcohols, ethers, and methyl-
amino derivatives (Table 2) were targeted because of
their accessibility from ester 35 which is readily available
in enantiomerically pure form.10 Data in Table 2 indi-
cate that the bridgehead position is highly tolerant to
substitution as high GR binding was observed for al-
most all analogues in both the oxygen (38–57) and nitro-
gen linked series (61–79). Enantiospecificity was again
observed, as the racemates of many of these compounds
were also evaluated and showed lower GR binding and
functional activity (data not shown). Also as previously
As a prelude to pharmacodynamic testing, selected com-
pounds were tested for oral bioavailability, initially in
the rat with subsequent testing in the dog (Table 3). The
whole brain to plasma ratio was also determined in the
rat. Bridgehead methoxyethyl ethers and amines showed
uniformly low bioavailability in the rat (F = 610%).15
Several of the methyl ethers demonstrated a better profile,
notably compounds 43 and 45, which had reasonable
brain/plasma ratios in the rat and respectable bioavail-
ability and T1/2 in the dog. Pharmacokinetic properties
were significantly better in the dog than in the rat for
the four compounds examined. The rat data did not cor-
relate well with in vitro microsomal clearance rates,
implying that absorption is the main determinant for bio-
availability in this series of compounds. The methoxy-
ethyl ether does appear to be a metabolic liability

R. D. Clark et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1312–1317
1317
Steinberg, N. G.; Buchschacher, P.; Fried, J. H.; Kent, G.
J.; Tishler, M. J. Am. Chem. Soc. 1963, 85, 120.
6. (a) Shah, N.; Scanlan, T. S. Bioorg. Med. Chem. Lett.
2004, 14, 5199; (b) Thompson, C. F.; Quraishi, N.; Ali, A.;
Tata, J. R.; Hammond, M. L.; Balkovec, J. M.; Einstein,
M.; Ge, L.; Harris, G.; Kelly, T. M.; Mazur, P.; Pandit, S.;
Santoro, J.; Sitlani, A.; Wang, C.; Williamson, J.; Miller,
D. K.; Yamin, T. D.; Thompson, C. M.; O’Neill, A.;
Zaller, D.; Forrest, M. J.; Carballo-Jane, E.; Luell, S.
Bioorg. Med. Chem. Lett. 2005, 15, 2163.
7. Kumar, V.; Bell, M. R.; Wetzel, J. R.; Herrmann, J. L.;
McGarry, R.; Schane, H. P.; Winneker, R. C.; Snyder, B.
W.; Anzalone, A. J. J. Med. Chem. 1993, 36, 3278.
8. (a) Barth, M. M.; Binet, J. L.; Thomas, D. M.; de Fornel,
D. C.; Samreth, S.; Schuber, F. J.; Renaut, P. P. J. Med.
Chem. 1996, 39, 2302; (b) Pfau, M.; Revial, G.; Guingand,
A.; d’Angelo, J. J. Am. Chem. Soc. 1985, 107, 273,
Compound 26 was obtained with an ee of 96% (chiral
HPLC analysis) which is consistent with the ee of >95%
for diketone 23 reported in Ref. 8a.
however, as compounds with this group showed rapid
microsomal clearance across species, most importantly
human microsomes.16 Although based on only three
examples (29, 44, 78), it also appeared that the tert-butyl
substituent on the benzenesulfonamide was detrimental
to brain penetration in the rat, possibly due to the molec-
ular size. It can be noted that the compounds with the best
in vivo pharmacokinetic profile (e.g., 43 and 45) have
modest GR functional activity relative to other ana-
logues; hence further optimization of the series is ongoing
in an attempt to improve this situation. Results of these
efforts, and pharmacodynamic testing, will be reported
in due course.
Acknowledgment
We thank Dr. Alec Oxford for his expert advice and
encouragement during the course of this work.
9. Zayia, G. H. Org. Lett. 1999, 1, 989.
10. Christoffers, J.; Scharl, H. Eur. J. Org. Chem. 2002, 1505,
The ee of 35 obtained by this procedure was >98% (chiral
HPLC analysis) which is consistent with the reported
value of 97% ee..
11. The optical purity of final compounds 38–57 and 61–79
was >98% ee on the basis of the ee of the starting ester 35
(Ref. 10). Intermediate 37 (Z = tert-butyl) had an ee of
99% (chiral hplc) confirming that the chiral integrity of the
system was maintained.
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13. Estrogen receptor: [3H]estradiol, Pan Vera 26467A ERa;
androgen receptor: [3H]dihydrotesterone, Pan Vera 24938
AR; mineralocorticoid receptor: [3H]aldosterone, Sf9 cells/
recombinant MR; progesterone receptor: [3H]progester-
one, Pan Vera 24900 PR.
14. The bridgehead methyl analogue corresponding to 1 had a
Ki of >10 lM in GR binding (unpublished results).
15. Methoxyethyl ethers (rat F%): 50 (8), 52 (0), 55 (2);
amines: 61 (0), 62 (5), 66 (0), 69 (0), 71 (4), 74 (2).
16. For example, methyl ether 43 showed 57% remaining after
a 30 min incubation with human microsomes, compared
to 7% remaining for the corresponding methoxyethyl ether
51.