Adamantane 11-β-HSD-1 inhibitors: Application of an isocyanide multicomponent reaction

Article abstract of DOI:10.1016/j.bmcl.2006.08.129

A series of potent and selective adamantane aminoamide 11-β-HSD-1 inhibitors has been optimized. Chemically these studies were expedited by utilizing readily obtained amino acids as starting materials or an isocyanide multicomponent reaction. Structure-ac

Full text of DOI:10.1016/j.bmcl.2006.08.129

Bioorganic & Medicinal Chemistry Letters 16 (2006) 5958–5962
Adamantane 11-b-HSD-1 inhibitors: Application of an
isocyanide multicomponent reaction
Bryan Sorensen,a Jeff Rohde,a Jiahong Wang,a Steven Fung,a Katina Monzon,a
William Chiou,a Liping Pan,b Xiaoqing Deng,b DeAnne Stolarik,c
Ernst U. Frevert,a, Peer Jacobsona and J. T. Linka,*
aMetabolic Disease Research, Abbott, 100 Abbott Park Road, Abbott Park, IL 60064, USA
bDrug Metabolism, Abbott, 100 Abbott Park Road, Abbott Park, IL 60064, USA
cExploratory Science, Abbott, 100 Abbott Park Road, Abbott Park, IL 60064, USA
Received 8 August 2006; revised 30 August 2006; accepted 31 August 2006
Available online 25 September 2006
Abstract—A series of potent and selective adamantane aminoamide 11-b-HSD-1 inhibitors has been optimized. Chemically these
studies were expedited by utilizing readily obtained amino acids as starting materials or an isocyanide multicomponent reaction.
Structure–activity relationship studies resulted in the discovery of dual human and mouse 11-b-HSD-1 potent and selective inhib-
itors like adamantane 11 and related compounds with high metabolic stability and robust pharmacokinetic profiles.
Ó 2006 Elsevier Ltd. All rights reserved.
Patients with Cushing’s syndrome have elevated circu-
lating glucocorticoid levels that cause a variety of
abnormalities including central/visceral obesity, insulin
resistance, hyperglycemia, and dyslipidemia amongst
others. The similarity of these symptoms to those ob-
served in patients with metabolic syndrome, diabetes,
and obesity have led numerous investigators to target
the glucocorticoid axis for research and potential ther-
apy. Recent research has focused on 11-b-hydroxyster-
oid dehydrogenase 1 (11-b-HSD-1) which is found
primarily in the liver, fat, and brain.1 11-b-HSD-1 cat-
alyzes the reduction of the glucocorticoid receptor
(GR) inactive 11-keto glucocorticoid cortisone to the
corresponding active glucocorticoid cortisol. The prere-
ceptor metabolism performed by this enzyme is respon-
sible for increasing local glucocorticoid levels relative
to circulating concentrations. Inhibitors of 11-b-HSD-
1 are being examined as a potential treatment for
metabolic syndrome, diabetes, obesity, and other indi-
cations and are currently under intense investigation.
11-b-HSD-2 is a related enzyme that catalyzes the re-
verse reaction. It is found primarily in mineralocorti-
coid sensitive tissues, like the kidney, where it lowers
local glucocorticoid concentrations to prevent cortisol
from activating mineralocorticoid receptors. Inhibition
of this enzyme leads to high blood pressure and other
deleterious consequences necessitating selectivity
against this dehydrogenase.
Multiple classes of 11-b-HSD-1 inhibitors have been dis-
covered (Fig. 1).2 Many of the early examples are ste-
roids like carbenoxolone (1), that are typically
unselective and inhibit 11-b-HSD-2 as well.3 In terms
of 11-b-HSD-1 selective compounds, multiple nonsteroi-
dal inhibitors have been discovered. This includes sul-
fonamides such as BVT.2733 (2),4 triazoles like 544
(3),5 and adamantanes such as 4.6 We have optimized
a series of adamantane amides as 11-b-HSD-1 inhibi-
tors.6 During our initial studies we learned that the sub-
stituents R2 and R3 had a dramatic effect upon cross
species potency, particularly in rodents. Therefore, we
set out to explore the SAR at this position and to dis-
cover simple methods to prepare a diverse set of ana-
logs. Two strategies in particular were explored.
Building the central a-amino amide portion from amino
acids and by a multicomponent reaction.
Keywords: 11-b-HSD-1 inhibitors; Adamantane; Multicomponent
reaction; Metabolism; HSD1 inhibitor; Hydroxysteroid dehydrogenase
type 1; Metabolic syndrome.
*
Corresponding author. Tel.: +1 847 935 6806; fax: +1 847 935
5165; e-mail: james.link@abbott.com
Present address: Novartis Pharmaceuticals, East Hanover, NJ 07936,
USA.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.08.129

B. Sorensen et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5958–5962
5959
acids like 10, which can be converted to primary amides
like 11.
CO2H
O
H
In order to further increase the diversity of available
analogs, a route to prepare these compounds in parallel
was developed. Multicomponent reactions are a power-
ful tool allowing a diverse set of analogs to be prepared
rapidly.9 In order to take advantage of an isocyanide
multicomponent reaction, similar to those originally dis-
covered by Ugi10 and McFarland,11 isocyanide 13 was
prepared. Commercially available hydroxyadamanta-
none 12 was converted to a 4:1 E:Z mixture of aminoad-
amantyl esters 9, by carbomethoxylation followed by
diastereoselective reductive amination. Acylation of
the amine with methyl formate followed by dehydration
with phosphorus oxychloride provided isocyanide 13 in
moderate yield diastereomerically pure after removal of
H
O
H
HO2C
O
Cl
1
H
N
N
S
O O
S
N
N
O
2
R2 R3
N
N N
N
H
N
R4
O
R5
R1
3
4
O
NH2
b
a
Figure 1. Inhibitors of 11-b-HSD1: carbenoxolone (1), BVT.2733 (2),
Merck compound 544 (3), and adamantanes 4.
MeO2C
9 (4:1 E:Z)
HO
12
In addition to the large number of commercially avail-
able amino acids, there are also numerous methods for
preparing nonnatural relatives, often enantioselectively.7
We sought to develop procedures to prepare analogs
from these readily available starting materials. For in-
stance, adamantanes 4, wherein R4 and R5 combine to
form a piperazine, can be prepared as shown in Scheme
1. Aminoester 5 can be treated with the previously
reported bis-triflate 6, according to a known procedure,8
to efficiently provide piperazine 7. The piperazine can
then be deprotected with phenylthiolate under mildly
basic conditions and arylated by several methods,
including nucleophilic aromatic substitution with 2-bro-
mo-5-trifluoromethyl-pyridine, to provide piperazine
acids like 8 after ester hydrolysis. The acid 8 can then
be coupled under standard amide formation conditions
to a 4:1 E:Z 4-amino-adamantane-1-carboxylic acid
methyl ester 9 (see Scheme 2 for its preparation). The
resulting amides then can be separated by column chro-
matography and hydrolyzed to provide adamantane
O
HN
NC
N
N
+
+
MeO2C
CF3
15
13
14
H
N
N
c
O
N
N
ROC
16 R = OH
17 R = NH2
CF3
d
Scheme 2. Reagents and conditions: (a) 30% oleum, HCO2H, 60 °C,
˚
1.5h; MeOH, 0 °C ! rt, 2h; NH3, 4 A molecular sieves, MeOH, 16h;
NaBH4, 0 °C ! rt, 2h; (b) methyl formate; Et3N, 50 °C, 12h, 42% (4
steps); POCl3, Et3N, CH2Cl2, ꢀ10 °C ! rt, 2h, 79%; (c) 1-(5-trifluo-
romethyl-pyridin-2-yl)-piperazine, cyclobutanone, AcOH, MeOH,
rt ! 70 °C, 12h, 22%; NaOH, THF, H2O, MeOH, rt, 16h, 100%;
(d) EDCI, HOBt, DMF, rt, 2h; NH4OH, 12h, 76%.
O
O S
MeO
a
N
b
MeO
NH2
+
O
N
N
NO2
OTf
S
O
O O
NO2
TfO
5
6
7
H
N
HO
NH2
N
N
c
+
O
N
N
O
N
N
ROC
MeO2C
CF3
CF3
8
9 (4:1 E:Z)
10 R = OH
11 R = NH2
d
Scheme 1. Reagents and conditions: (a) Na2CO3, CH3CN, 60 °C, 12h, 80%; (b) PhSH, K2CO3, DMF, rt, 1h; 2-bromo-5-trifluoromethyl-pyridine,
K2CO3, DMSO, 80 °C, 12h, 59% (2 steps); NaOH, THF, H2O, MeOH, 60 °C, 16h, 100%; (c) TBTU, i-Pr2NEt, DMF, rt, 12h, 75%; NaOH, THF,
H2O, MeOH, 60 °C, 12h, 53% (+Z-isomer); (d) EDCI, HOBt, DMF, rt, 2h; NH4OH, 12h, 78%.

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B. Sorensen et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5958–5962
Table 1. Human and mouse HSD1 and HSD2 inhibition for compounds 7–15
R3 R4
H
N
N
R5
N
N
N
O
R1
R2
R5 = A
R5 = B
CF3
Compound R1
R2
R3,a
Me
R4,a
R5 h-HSD1 h-HSD2
m-HSD1 m-HSD2
h-HSD1 HEK % Remaining
MLMc
Kib, nM IC50b, nM Kib, nM
IC50b, nM IC50b, nM
18
19
20
21
10
22
23
11
24
OH
OH
H
H
Me
A
A
A
B
B
B
B
B
B
13
2
3600
8300
4
2
>100,000
26,000
>100,000
780
28
7
19
–CH2– –CH2–
–CH2– –CH2–
ND
ND
89
H
OH
H
6
>100,000
21,000
>10,000
ND
58
390
39
CO2H
CO2H
H
Me
Me
13
7
180
500
1700
5
H
–CH2– –CH2–
–CH2– –CH2–
3200
ND
45
98
CO2H
H
250
9
1900
45
ND
65
CO2NH2
CO2NH2
H
Me Me
–CH2– –CH2–
>10,000
>10,000
>100,000
3600
>100,000
90,000
H
CO2NH2 –CH2– –CH2–
8
13
15
1500
22
490
70
ND
a When R3 and R4 are –CH2– it represents a substituent where R3 and R4 are linked to form a cyclopropane.
b Values are means of two experiments (ND, not determined).
c Percent remaining after a 30 min incubation with mouse liver microsomes (MLM).
Table 2. Human and mouse HSD1 and HSD2 inhibition for compounds 7, 8, 12, 13, and 16–23
F
R2 R3
N
H
N
N
F
R4
N
N
O
R1
R2
R4 = B
R4 = A
CF3
Compound
R1
R3
R4
h-HSD1
Kia, nM
h-HSD2
IC50a, nM
m-HSD1
Kia, nM
m-HSD2
IC50a, nM
h-HSD1 HEK
IC50a, nM
% Remaining
MLMb
21
25
26
16
27
23
28
29
17
30
31
32
CO2H
CO2H
Me
Et
Me
H
A
A
A
A
A
A
A
A
A
A
B
12
120
18
17
22
9
>10,000
65,000
24,000
180
700
580
270
580
5
650
5400
39
1800
87
89
ND
ND
ND
ND
65
CO2H
CO2H
CO2H
Cyclopropyl
CBc
CPd
Me
H
2700
1700
CBc
CPd
Me
H
27,000
15,000
37
1100
3600
280
36
CO2NH2
CO2NH2
CO2NH2
CO2NH2
CO2NH2
CO2H
>10,000
>100,000
>100,000
34,000
Et
6
15
5
>100,000
>100,000
8900
24
38
88
93
Cyclopropyl
H
6
CBc
CPd
Et
CBc
CPd
H
7
3
26
19
29
91
42
73
5
50,000
100,000
>10,000
14,000
7700
>100,000
ND
ND
ND
1200
3
640
36
CO2NH2
Et
H
B
a Values are means of two experiments (ND, not determined).
b Percent remaining after a 30 min incubation with mouse liver microsomes (MLM).
c When R2 and R3 are CB it represents a substituent where R2 and R3 are linked to form a cyclobutane.
d When R2 and R3 are CP it represents a substituent where R2 and R3 are linked to form a cyclopentane.
the Z-isomer by chromatography. Isocyanide 13 under-
goes a multicomponent reaction with aldehydes and ke-
tones, like cyclobutanone 14, and an amine, like aryl
piperazine 15, to provide adamantane aminoamides,
such as 16, after ester hydrolysis.11 The acids can then
be converted to the corresponding amides by standard
coupling procedures.
either penetrated, or were excluded from, the central
nervous system (CNS) to determine the role of
inhibition of brain 11-b-HSD-1. To simplify preclinical
compound evaluation, compounds with mouse
11-b-HSD-1 potency and selectivity over m-11-b-HSD-
2 that matched their human potency and selectivity were
sought. Dual species potent and selective compounds
have been difficult to identify in other inhibitor series.2,4
Identifying long-acting inhibitors against 11-b-HSD-1 is
also challenging. The steroid binding site, where many
classes of inhibitors bind, is lipophilic as are many of
We set out to discover long-acting inhibitors that would
potently inhibit 11-b-HSD-1 in the fat and liver. It was
further hoped that compounds could be identified that

B. Sorensen et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5958–5962
5961
the inhibitors. The compound lipophilicity often leads to
poor metabolic stability making identifying compounds
with robust PK profiles difficult.
The potency of compounds was measured in assays that
quantitated the inhibition of conversion of radiolabeled
cortisone to cortisol (truncated h- and m-11-b-HSD-1)
or disappearance of cortisol (h- and m-11-b-HSD-2).
Radioactive cortisol concentrations were determined
by a scintillation proximity assay (SPA) employing an
anticortisol monoclonal antibody and SPA beads coated
with anti-mouse antibodies. Cellular activity was mea-
sured in HEK293 cells that are stably transfected with
h-11-b-HSD-1. Cortisone is added and inhibition of
the formation of cortisol is measured by fluorescent
polarization immuno-assay.
Piperidine substituted inhibitor 18 has an excellent bio-
chemical profile with excellent h- and m-11-b-HSD-1
potency and good h- and m-11-b-HSD-2 selectivity with
potent cellular activity (Table 1). However, it has poor
metabolic stability as assessed in mouse liver
microsomes. SAR of related compounds indicated the
dimethyl substituents at R3 and R4 were important for
m-11-b-HSD-1 activity. To mimic this group, the
corresponding cyclopropanes 19 and 20 were prepared
and they maintained a similar profile. In order to
improve the metabolic stability, more polar substituents
were incorporated at both ends of the compounds. The
adamantane acid 21 has excellent h-11-b-HSD-1
potency and h-11-b-HSD-2 selectivity, moderate m-11-
b-HSD-1 potency, and poor m-11-b-HSD-2 selectivity.
It also has excellent metabolic stability. Examination
of the corresponding cyclopropane 10 indicates it main-
tained the human HSD profile but unfortunately did not
improve the rodent profile. The Z-adamantane 22 was
dramatically less potent, as are many of the Z-substitut-
ed compounds like 20 and 24. The corresponding
amides 23, 11, and 24 are dual potent and selective.
Scheme 3. Mouse pharmacokinetic data for adamantane acid 10.
life (2.9h), low iv clearance (0.1L/h kg), and a low vol-
ume of distribution. The data indicate that this series
of compounds can provide long-acting inhibitors for
pharmacologic evaluation of 11-b-HSD-1 inhibition.
In summary, a potent series of adamantane 11-b-HSD-1
inhibitors was optimized by employing chemistry that
relies upon amino acids as starting materials and a multi-
component reaction. Dual human and mouse 11-b-HSD-
1 potent and selective amides like 11 were discovered that
also have excellent cellular potency and metabolic
stability. Adamantane acids, like arylpiperazine 10, have
an excellent human biochemical profile and a robust
pharmacokinetic profile.
Acknowledgment
Seble Wagaw, Kenneth Engstrom, Frank Kerdesky,
and Dan Plata are acknowledged for developing and
executing large-scale syntheses of intermediates. David
Beno is thanked for assisting with the pharmacokinetic
experiment.
The compounds shown in Table 2 were prepared via a
multicomponent reaction and allowed for the assess-
ment of a broad range of substituents for R2 and R3.
Large (e.g., R2 = Ph, R3 = H) or polar substituents
(e.g., R2 = CH2OH, R3 = H) had poor activity and small
nonpolar groups were potent (data not shown). For
adamantane acids 16, 21, and 25–27, human potent
and selective compounds were obtained. However, vary-
ing the substituents did not dramatically improve the
mouse potency or selectivity. The adamantane amides
17, 23, and 27–30 were all both human and mouse po-
tent and selective with excellent cellular potency. Fur-
thermore, these compounds have robust metabolic
stability. Varying R4 to a smaller more lipophilic group
(difluoropiperidine) in compounds 31 and 32 resulted in
an acid with poor potency and an amide with excellent
potency and selectivity.
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