Adamantane sulfone and sulfonamide 11-β-HSD1 Inhibitors

Article abstract of DOI:10.1016/j.bmcl.2006.10.008

Potent and selective adamantane sulfone and sulfonamide inhibitors of 11-β-HSD-1 have been discovered. Selected compounds from these series have robust pharmacokinetic profiles and strongly inhibit liver, fat, and brain HSD1 for extended periods after ora

Full text of DOI:10.1016/j.bmcl.2006.10.008

Bioorganic & Medicinal Chemistry Letters 17 (2007) 527–532
Adamantane sulfone and sulfonamide 11-b-HSD1 Inhibitors
Bryan Sorensen, Martin Winn, Jeff Rohde, Qi Shuai, Jiahong Wang, Steven Fung,
Katina Monzon, William Chiou, DeAnne Stolarik, Hovis Imade, Liping Pan,
Xiaoqing Deng, Linda Chovan, Kenton Longenecker, Russell Judge, Wenying Qin,
Michael Brune, Heidi Camp, Ernst U. Frevert, Peer Jacobson and J. T. Link*
Abbott, Dept. 47F, Bldg. AP-10, Rm. 301, 100 Abbott Park Road, Abbott Park, IL 60064-6098, USA
Received 29 August 2006; revised 3 October 2006; accepted 5 October 2006
Available online 7 October 2006
Abstract—Potent and selective adamantane sulfone and sulfonamide inhibitors of 11-b-HSD-1 have been discovered. Selected
compounds from these series have robust pharmacokinetic profiles and strongly inhibit liver, fat, and brain HSD1 for extended
periods after oral dosing.
Ó 2006 Elsevier Ltd. All rights reserved.
6
Recently, selective inhibitors of 11-b-hydroxysteroid
dehydrogenase (11-b-HSD1) have been studied as a po-
tential treatment for metabolic disease. Interest in this
the 11-b-HSD1 selective inhibitors BVT.2733 2 and
544 3 (Fig. 1).
7
1
target has been heightened by the results obtained dur-
ing the analysis of genetically altered rodents and inhib-
CO H
2
2
itor pharmacology. Particularly notable amongst these
experiments are those conducted in adipose 11-b-HSD1
overexpressing mice, whose enzyme expression mimics
O
3
H
that seen in obese humans. The phenotype of these mice
is strikingly similar to the human metabolic syndrome
where the mice have visceral obesity and hyperphagia
that is exacerbated by a high fat diet. The mice also
are insulin resistant, hyperlipidemic, and hypertensive.
O
H
HO C
O
2
H
Cl
1
11-b-HSD1 knockout mice have also been generated
and are resistant to obesity or stress induced hyperglyce-
mia and have improved insulin sensitivity and glucose
4
tolerance. Additionally, the animals have an interesting
H
N
N
S
lipid profile (decreased triglyceride and increased HDL)
and resist diabetes and weight gain, despite consuming
more calories. These mice also show reduced age-related
learning impairment. Inhibitors from different chemical
series have also been effective in rodent models of diabe-
tes, obesity, and learning. Amongst the most studied
compounds reported to date are the nonselective steroi-
O O
S
N
N
O
2
R2 R3
N
N N
N
H
N
R4
5
dal 11-b-HSD1 and 2 inhibitor carbenoxolone (1) and
O
O
R5
H N
2
3
4
Keywords: 11-b-HSD-1; HSD1; 11-b-Hydroxysteroid dehydrogenase;
HSD1 inhibitor; Adamantane; Sulfone; Sulfonamide.
Figure 1. 11-b-HSD1 inhibitors. The steroidal 11-b-HSD2 unselective
inhibitor carbenoxolone (1) and the selective nonsteroidal inhibitors
BVT.2733 2, 544 3, and adamantane amide 4.
*
Corresponding author. Tel.: +1 847 935 6806; fax: +1 847 935
165; e-mail: james.link@abbott.com
5
0
960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.10.008

528
B. Sorensen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 527–532
tane. These groups tend to reduce permeability (and of-
F
ten potency). During our optimization, we sought to
strike a balance between permeability and metabolic sta-
bility. A 1-carboxamido adamantane substituent (e.g.,
amides 4) worked well in vitro, but it suffered cleavage
in vivo and led us to explore the sulfone and sulfon-
amide analogs reported herein. We have also been inter-
ested in tissue selective inhibitors with different
durations of action. Long-acting compounds that
potently inhibit liver, fat, and brain 11-b-HSD1 offer a
starting point for finding compounds with selective
exposure profiles.
NH2
+
HO
O
O
HO
O
Cl
6
5
(4:1 E:Z)
F
H
N
a
O
Cl
R
R
7
8
R = OH
b
d
A representative adamantane sulfone synthesis is shown
in Scheme 1. A 4:1 E:Z mixture of 5-hydroxy-2-adaman-
tamine 5, obtained from reductive amination of 5-hy-
droxy-2-adamantanone, is coupled to carboxylic acids
R = O CCF3
2
F
H
N
8
like ether 6. These ethers are easily prepared from the
corresponding phenols using 1,1,1-trichloro-2-methyl-
c
O
O
Cl
9
propan-2-ol under precedented reaction conditions.
The tertiary alcohol was then converted to the corre-
sponding trifluoroacetate 8, which underwent a substitu-
tion reaction when treated with NaSMe in
trifluoroacetic acid. The oxidation of the resultant sul-
fide 9 provided sulfone 10 in excellent yield. These steps
were scaled up effectively, all proceeding in the yields
quoted when run on scales greater than 10 g.
9
1
R = SMe
0 R = SO Me
2
Scheme 1. Reagents and conditions: (a) TBTU, DMF, rt, 12 h, 70%;
b) (CF CO) CO H, 115 °C, 12 h,
O, TFA, 80 °C, 1 h; (c) NaSMe, CF
3% (two steps); (d) NaBO Æ4H O, CH CO H, rt, 1.25 h, 97%.
(
3
2
3
2
8
3
2
3
2
Our efforts to identify potent and selective inhibitors of
1-b-HSD1 have centered upon the optimization of a
series of 2-adamantylamino amides. Initially, these
compounds were chosen for further study due to their
permeability, which we hoped would give them the abil-
ity to penetrate and inhibit 11-b-HSD1 in fat.
1
We were also interested in the corresponding sulfona-
mides, like 18, which proved more difficult to prepare
(Scheme 2). Although adamantane sulfonyl chlorides
are readily prepared, they do not couple effectively with
amines. Senanayake and coworkers developed chemistry
able to overcome this problem in less functionalized
systems and we adopted their approach. For these
analogs, 2-hydroxy-5-adamantanone 11 was converted
into bromoketal 12. Insertion, employing Rieke zinc,
8
1
0
However, the metabolic stability of adamantane is fre-
quently poor and is best improved in this series by the
judicious placement of charged groups on the adaman-
Ts
N
O
S
O
O
1
3 (3:2 dr)
O
TsHN
O
O
O
O
S
O
a
b
c
O
d
O
Br
HO
H NOS
2
11
12
14 (1:1 dr)
15
Cl
H
Cl
NH2
+
N
O
e
HO
O
H NO S
O
H NO S
2 2
2
2
O
18
16
17
Scheme 2. Reagents and conditions: (a) 48% HBr, H
THF, rt, 48 h; 14, THF, ꢀ50 °C, 12 h, 34%; (c) LiNH
O, THF, 60 °C, 12 h, 81%; H , NH , Pd/C, MeOH, rt, 48 h, 65%; (e) TBTU, i-Pr
2
O, 100 °C, 12 h, 49%; HOCH
, Fe(NO Æ9H
O, THF, ꢀ45 ! ꢀ78 °C, 2 h, 72%; (d) OsO
NEt, DMF, rt, 12 h, 65%.
2
CH
2
OH, cat. p-TsOH, PhH, 80 °C, 4 h, 98%; (b) Rieke zinc,
2
3
)
3
2
4
, NMO, THF, rt, 12 h; 1 M HCl,
H
2
2
3
2

B. Sorensen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 527–532
529
provided the corresponding adamantyl zinc reagent that
coupled with the 1,2,3-oxathiazolidine-2-oxides 13
sulfonamide, and finally by deprotection. Alternatively,
the thioacetate 20 could be converted to a key sulfone
intermediate 22 by cleavage/alkylation with methyl
iodide, oxidation to the sulfone, and hydrogenolytic
deprotection.
(
3:2 dr) to provide sulfinate esters 14 (1:1 dr). Treatment
with lithium amide then provided sulfinamides 15,
which underwent oxidation, deprotection, and reductive
amination to provide aminosulfonamide 16. This
intermediate allowed for the preparation of a wide
variety of inhibitors. For instance, coupling with acid
Compounds were assayed in human and mouse HSD1
(h- and m-HSD1) and HSD2 assays that assessed the
ability of a compound to inhibit the interconversion be-
1
7 led to the potent 11-b-HSD1 inhibitor amide 18.
8
tween cortisone and cortisol. A cellular assay in HEK
Due to the expense and difficulties encountered in scal-
ing up these reactions a more efficient protocol was
sought (Scheme 3). The 4:1 E:Z mixture of 5-hydroxy-
cells overexpressing h-HSD1 was also employed. Mouse
liver microsomes were utilized as an initial screening sys-
tem for metabolic stability.
2
-adamantamine 5 was protected and the diastereomers
chromatographically separated. After mesylation pro-
vided 19, the corresponding thioacetate 20 was prepared
by heating in thioacetic acid. This intermediate was effi-
ciently converted to the key sulfonamide intermediate 16
by removal of the acetate group. This was followed by
reaction of the thiol with chloramine, oxidation to the
Sulfone 10 has excellent potency against h- and m-
HSD1 and good selectivity over h- and m-HSD2 (Table
1). The compound also has moderate cellular potency
and metabolic stability. Increasing the size of the sulfone
group typically decreased potency, although moderately
potent compounds such as 23–25 were found. Monosub-
NH2
NHCBz
NHCBz
NH2
a
b
c
HO
MsO
AcS
H2NO2S
5
(4:1 E:Z)
19
20
16
d
NH2
NHCBz
e
MeO S
2
MeS
22
21
Scheme 3. Reagents and conditions: (a) CbzCl, Na
CbzCl, Na CO
O, rt, 12 h, 48% (three steps); H
, Pd/C, MeOH, EtOAc, rt, 12 h, 100%.
2
CO
3
, THF, rt, 12 h, 76% (pure E); MsCl, Et N, CH
3
2
Cl
2
, 0 °C ! rt, 12 h; (b) AcSH, 70 °C, 12 h;
O, 0 °C ! rt, 1 h; MCPBA, EtOH,
, NMO, THF, rt, 2 h, 83% (two steps);
2
3
, THF, rt, 12 h, 75% (three steps); (c) MeSNa, MeOH, rt, 1 h; NH
4 3 2
OH, NaOCl, Et N, THF, H
H
H
2
2
, Pd/C, MeOH, rt, 12 h, 100%; (d) NaOMe, MeI, MeOH, rt, 12 h; (e) OsO
4
2
Table 1. Human and mouse 11-b-HSD-1 and 11-b-HSD-2 assay results for compounds 10 and 23–31
H
N
R2
R1
O
S
O
O
1
R
2
R
Compound
h-HSD1 h-HSD2
a
i
m-HSD1 m-HSD2
a
i
h-HSD1 HEK % remaining
a
a
(nM) IC50 (nM)
a
b
K
K
(nM) IC50 (nM) IC50 (nM)
MLM
10
23
24
25
26
27
28
20
30
31
Me
Et
2-Cl, 4-F phenoxy
2-Cl, 4-F phenoxy
2-Cl, 4-F phenoxy
7
26,000
15,000
3300
4
7
>100,000
>100,000
>100,000
87,000
98
450
300
500
120
530
410
120
690
210
57
26
8
ND
59
CH
2
CONH
2
4
(CH
Me
Me
Me
Me
Me
Me
2
)
3
-morpholine 2-Cl, 4-F phenoxy
2-Cl phenoxy
3-Cl phenoxy
110
5
15,000
5400
38
2
<1
ND
7
>100,000
>100,000
>100,000
>100,000
>100,000
>100,000
8
17,000
65,000
>100,000
>100,000
21,000
10
8
4-Cl phenoxy
7
70
2-CF phenoxy
2-OMe, 4-F phenoxy
2-F, 4-Cl phenoxy
3
7
3
ND
ND
63
20
11
7
8
a
Values are means of at least two experiments (ND, not determined).
Percent remaining after a 30 min incubation with mouse liver microsomes (ND, not determined).
b

530
B. Sorensen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 527–532
stitution of the phenyl ether with small electron-with-
drawing groups maintained potency as in 26–29 and
substituents in the 4 position had the greatest effect upon
metabolic stability, suggesting this is a site of metabo-
lism. Disubstituted analogs such as 10, 30, and 31 were
also potent and selective.
site with its central amide interacting with the residues
responsible for substrate ketone reduction (Fig. 2).
The sulfonamides display a similar SAR as the sulfones
(Table 2). The parent sulfonamide phenyl ether 32 has
good potency against h- and m-HSD1 with good selec-
tivity over h- and m-HSD2. It has modest cellular poten-
cy and moderate metabolic stability. Small electron-
withdrawing groups on the phenyl ether improve poten-
cy as in aryl chlorides 33, 34, and 18. Metabolic stability
is similarly high in the 4-substituted analog, again impli-
cating it as a site of metabolism. Mono- or disubstitution
of the sulfonamide, as in 35 and 36 respectively, yields
modest changes in potency, but dramatically reduces
metabolic stability. Acyl sulfonamide 37, predicted to
have good metabolic stability, was unfortunately not
potent. Removing the ether oxygen decreased mouse
HSD1 potency as in amide 38. Polysubstituted arenes
like 40 and 41 showed some of the best overall profiles,
having better metabolic stability than the more cellularly
potent monosubstituted analog 39.
An X-ray crystal structure of sulfone 10 bound to h-
HSD1 was obtained (pdb code 2ILT). This structure
indicates that the inhibitor binds to the steroid binding
Ser 170
Adamantane sulfone and sulfonamide inhibitors with
the best combination of potency, selectivity, and meta-
bolic stability were studied in mouse pharmacokinetic
experiments (Table 3). Sulfonamide 40 had a good vol-
ume of distribution consistent with tissue penetration
and a moderate half-life and clearance. Its bioavailabil-
ity is moderate but improved upon by sulfonamide 18,
which may undergo enterohepatic recirculation. Sulfone
Tyr 183
Tyr 177
1
0 has a similar pharmacokinetic profile and has excel-
lent bioavailability. A study in monkeys also showed a
continued trend of excellent bioavailability, longer
half-life, lower clearance, and a volume of distribution
consistent with tissue penetration.
Figure 2. Crystal structure of sulfone 10 bound to h-11-b-HSD1.
Atoms are colored according to atom type and the components differ
by carbon atom colors: the protein is gray, the NADP+ cofactor is
cyan, and compound 16 is green. The protein surface is also colored
according to atom type.
In order to determine the reason for the improved half-
life in monkeys, the metabolic stability of sulfone 10 was
Table 2. Human and mouse 11-b-HSD-1 and 11-b-HSD-2 assay results for compounds 18 and 32–41
R2
N
R3
R1
N
O
S
O
O
1
R
2
R
3
R
Compound
h-HSD1
a
i
h-HSD2
a
IC50 (nM)
m-HSD1
a
i
m-HSD2
a
IC50 (nM)
h-HSD1 HEK
a
IC50 (nM)
% remaining
b
MLM
K
(nM)
K
(nM)
32
33
34
18
35
36
37
38
39
40
41
H
H
H
H
H
H
Me
H
H
H
H
H
Phenoxy
21
4
59,000
5500
6300
13
2
>100,000
>100,000
>100,000
>100,000
>100,000
100,000
580
83
62
36
H
2-Cl phenoxy
3-Cl phenoxy
4-Cl phenoxy
4-Cl phenoxy
4-Cl phenoxy
4-Cl phenoxy
Ph
H
4
6
320
230
620
560
ND
420
54
ND
96
H
5
16,000
85,000
60,000
ND
5
Me
Me
Ac
H
8
8
<1
<1
ND
ND
38
14
170
8
21
110
210
3
ND
>100,000
25,000
>100,000
9000
>100,000
>100,000
>100,000
>100,000
H
2-OCF
2-Cl, 4-F phenoxy
2,6 Di-Cl, 4-F phenoxy
3
phenoxy
7
H
6
3
125
190
61
55
H
3
2
a
Values are means of at least two experiments (ND = not determined).
Percent remaining after a 30 min incubation with mouse liver microsomes (ND, not determined).
b

B. Sorensen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 527–532
Table 3. Pharmacokinetic results for sulfonamides 40 and 18 and sulfone 10
531
a
a
a
a
a
a
Compound
Species
Dose (mpk)
iv t1/2 (h)
V
ss (L/kg)
V
b
L/kg
iv CLp (L/h/kg)
po AUC (lg h/mL)
F (%)
40
18
10
10
Mouse
Mouse
Mouse
Monkey
10
5 iv, 10 oral
2.8
1.8
1.0
5.1
2.6
2.1
1.5
2.7
3.5
2.1
1.7
3.1
0.9
0.8
1.1
0.4
7.0
18.3
8.9
61
150
100
109
10
2.5
6.81
a
Values are means obtained from samples taken from three animals.
Table 4. Metabolic stability results for compound 10
Acknowledgments
a
Intrinsic clearance (L/h/kg)
Species
Liver microsomes
Hepatocyte
Rob Gregg is acknowledged for suggesting methods for
the preparation of adamantane sulfonamides. Larry
Solomon, Karl Walter, and Diane Bartlet are thanked
for the cloning and expression of the h-HSD1 construct
used in the crystallography experiments. Steve Cepa and
Dr. Lan Gao are thanked for determination of the cor-
tisol levels in ex vivo samples. Robin Shapiro, Victoria
Knourek-Segal, Tom Fey, Brian Droz, and Kelly Lar-
son are acknowledged for their assistance with the ex vi-
vo experiments. David Beno and Frank Kerdesky are
thanked for the design of pharmacokinetic experiments
and providing multigram quantities of an early interme-
diate, respectively.
Mouse
Monkey
Human
6.0
1.5
1.6
0.2
0.1
ND
a
Values are means of three experiments (ND, not determined).
Table 5. Ex vivo study in DIO mice for compounds 10 and 40
a
Compound
% inhibition
Liver (1, 7, 16 h) Fat (1, 7, 16 h) Brain (1, 7, 16 h)
1
4
0
0
95, 95, 89
70, 78, 82
87, 93, 86
62, 88, 93
90, 90, 77
29, 48, 73
a
Values are means from samples taken from two animals.
References and notes
assessed in mouse and monkey microsomes and hepato-
cytes (Table 4). The compound shows greater stability in
monkey microsomes relative to mouse, which is similar
to the trend observed with other adamantanes. Human
liver microsomes give a similar metabolic stability to
monkey, and little difference was noted in hepatocytes.
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and mouse 11-b-HSD1. Representative members of
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