Synthesis and structural activity relationship of 11β-HSD1 inhibitors with novel adamantane replacements

Article abstract of DOI:10.1016/j.bmcl.2006.07.062

A series of structurally novel and metabolically stable bridged bicyclic carbocycle and heterocycle adamantane replacements have been synthesized and biologically evaluated. Several of these compounds exhibit excellent human and mouse 11β-HSD1 potency and

Full text of DOI:10.1016/j.bmcl.2006.07.062

Bioorganic & Medicinal Chemistry Letters 16 (2006) 5408–5413
Synthesis and structural activity relationship of 11b-HSD1
inhibitors with novel adamantane replacements
Vince S. C. Yeh,* Ravi Kurukulasuriya, David Madar, Jyoti R. Patel, Steven Fung,
Katina Monzon, William Chiou, Jiahong Wang, Peer Jacobson, Hing L. Sham and J. T. Link
Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, AP-10,304B, Abbott Park, IL 60064, USA
Received 1 June 2006; accepted 20 July 2006
Available online 4 August 2006
Abstract—A series of structurally novel and metabolically stable bridged bicyclic carbocycle and heterocycle adamantane replace-
ments have been synthesized and biologically evaluated. Several of these compounds exhibit excellent human and mouse 11b-HSD1
potency and 11b-HSD2 selectivity.
Ó 2006 Elsevier Ltd. All rights reserved.
In the preceding communication, the synthesis and bio-
logical evaluation of heterocycle-containing adaman-
Cl
H
H
N
N
tane-based 11b-hydroxysteroid dehydrogenase type 1
(11b-HSD1) inhibitors were described.1 A number of
modifications were made on adamantane amide lead
structure 1 (Fig. 1) which led to compounds with signif-
icant improvements in pharmacokinetic (PK) profiles.
One structural commonality with the described inhibi-
tors is the adamantane head group. Adamantane-based
11b-HSD1 inhibitors have also been reported by several
groups working in this area (Fig. 1).2 Due to its hydro-
phobic nature, the unsubstituted adamantane group is
metabolically unstable in vivo. We have improved the
metabolic stability issue by placing a polar group such
as a primary carboxamide at the 1 position of the ada-
mantane. We are intrigued by the possibility of intro-
ducing other ring systems in our structural activity
studies based on 1. In this communication, we describe
our efforts in discovering a number of potent and meta-
bolically stable 11b-HSD1 inhibitors with structurally
novel adamantane replacements.
O
O
N
O
O
H N
2
1
2
N
N
N
3
Figure 1. Adamantane-based 11b-HSD1 inhibitors.
tions on the ring to stabilize the hydrophobic ring from
metabolism, to increase water solubility and increase
potency by polar interactions with the enzyme.
We designed these rings with C2 symmetry to simplify
stereochemical issues. We explored the structures of
these rings in increasing complexity going from monocy-
clic to bicyclic to bridged bicyclic.
Our strategy is to synthesize a number of carbocycles
and heterocycles of various ring shapes and sizes to ex-
plore the hydrophobic binding pocket of the enzyme.
These carbocycles and heterocycles are substituted with
a polar group at different positions and spatial orienta-
We initially targeted a mono-cyclic eight-membered ring
which was synthesized from commercially available diol
4. Mono-protection of 4, followed by oxidation of the
alcohol, gave ketone 5 which was converted into nitrile
6 by TOSMIC homologation3 followed by deprotection.
The alcohol 6 was then transformed into the amine 7 by
oxidation followed by reductive amination (Scheme 1).
Keywords: 11b-HSD1; Adamantane replacements; Metabolic stability.
*
Corresponding author. Tel.: +1 847 937 5567; fax: +1 847 938
1674; e-mail: vince.yeh@abbott.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.07.062

V. S. C. Yeh et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5408–5413
5409
HO
NC
O
was then converted into a mixture of syn and anti iso-
mers of amine 14 using standard conditions.
a,b
e, f
c,d
OH
OH
OTBS
4
6
5
With the above ring systems in hand, we then set to
synthesize several 1,4-disubstituted bridged bicyclic
six-membered rings which more closely resemble the
adamantane carboxamide lead 1 in terms of the distance
between the polar head group and the acyl side chain.
We utilized an efficient double annulation reaction of
enamines with dibromide 18 to synthesize the following
three bridged bicycles (Scheme 4). The bicyclo[3.2.1]-
octane system was derived from enamine 15 to give
the endo ketoester 19.8 Ketone 19 was converted into
amine 22 via reductive amination which gave a 5:1
mixture of isomers favoring the shown anti isomer.
NC
NH
2
7
Scheme 1. Reagents and conditions: (a) i—NaH, THF, rt, 3 h; ii—
TBSCl, 0 °C to rt, 5 h, 90%; (b) TPAP (5 mol%), NMO, molecular
sieves, CH2Cl2, rt, 3 h, 80%; (c) TOSMIC, KO-t-Bu, DME, MeOH,
50 °C, 3 h, 74%; (d) TBAF, THF, rt, 2 h, 90%; (e) TPAP (5 mol%),
NMO, molecular sieves, CH2Cl2, rt, 3 h, 75%; (f) NH4OAc, NaC-
NBH3, MeOH, rt, 12 h, 90%.
Amine 7 was isolated and used as a mixture of two syn
and anti isomers.
In a similar fashion, the bicyclo[3.3.1]nonane 20 was ob-
tained from enamine 16 in good yields.9 Reductive ami-
nation of ketone 20 gave a 3:1 mixture of amines 23 and
24 favoring the syn isomer 23. The 3-oxa-bicy-
clo[3.3.1]nonane 21 was synthesized following the same
strategy.10 Enamine 17 was found to be substantially
less stable than the carbocyclic counterparts 15 and 16,
hence affecting the yield of 21.
A bicyclo[5.1.0]octane ring system was synthesized from
known diene 8 (Scheme 2).4 Ring closing metathesis,
using first generation Grubb’s catalyst5 gave a good yield
of the desired seven-membered ring 9. Rh (I)-catalyzed6
[2 + 1] cyclopropanation gave the bicyclo[5.1.0]octane
ring, and after removal of the protecting group, the iso-
mers were separated. The major isomer is the all trans iso-
mer shown (10) as determined by NOE studies. Alcohol
10 was then converted into amine 11 as a near 1:1 mixture
of isomers from unselective reductive amination.
Scheme 5 shows the conversion of bridged bicyclic
ketones 20 and 21 into anti-substituted amines 27 and
28. Ketone 20 was protected as a dimethyl ketal and
the ester group was epimerized under basic condition
to give the exo isomer 25 (Scheme 5). After deprotection
and imine formation, the trans amine was installed via a
highly selective hydrogenation of methoxy imine 26
using Raney nickel to give 27 in good overall yields.
Ketone 21 was epimerized and converted to amine 28
following the same reaction sequence as shown for
amine 27. The selectivity in the methoxy imine hydroge-
nation step was noticeably lower than the carbocylic
The bicyclo[3.3.1]nonane system was synthesized from
adamantan-2-one 12 (Scheme 3). Bayer–Villeger oxida-
tion7 followed by methanolysis gave ester 13 which
OH
OTBDPS
OH
a, b
c, d
H
H
H
H
CO Et
2
8
9
10
O
EtO C
NH
N
X
2
2
a
O
H
CO Et
2
e, f
EtO C
2
19
EtO C
20
n
H
H
H
18
H
Br
Br
11
2
O
CO Et
2
15 X = CH , n = O
2
16 X = CH , n = 1
17 X = O, n = 1
2
Scheme 2. Reagents and conditions: (a) Cl2(PCy3)2Ru@CHPh
(5 mol%), CH2Cl2, 45 °C, 5 h, 80%; (b) TBDPSCl, imidazole, THF,
rt, 5 h, 90%; (c) ethyl diazoacetate (syringe pump), Rh2(OAc)4,
CH2Cl2, rt, 6 h, 75%; (d) TBAF, THF, 2 h, 85%; (e) (COCl)2, DMSO,
Et3N, CH2Cl2, À78 °C to rt, (Swern oxidation), 83%; (f) NH4OAc,
NaCNBH3, MeOH, rt, 12 h, 90%.
21
O
NH
2
b
H
19
H
22
EtO C
2
5:1 dr
H
H
MeO C
MeO C
NH
H
2
2
2
b
EtO C
EtO C
2
2
O
20
OH
H
NH
2
c, d
a, b
23
24
NH
2
12
13
14
23:24 = 3:1
Scheme 3. Reagents and conditions: (a) MCPBA, CH2Cl2, rt, 5 h; (b)
NaOMe, MeOH, rt, 72%, two steps; (c) Swern oxidation; (d) NH4OAc,
NaCNBH3, MeOH, rt, 85%, two steps.
Scheme 4. Reagents and conditions: (a) i—Et3N, CH3CN, reflux, 12 h;
ii—AcOH, water, reflux, 1 h, 75% for 19 and 20, 55% for 21; (b)
NH4OAc (10 equiv), NaCNBH3 (4 equiv), MeOH, rt, 92%.

5410
V. S. C. Yeh et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5408–5413
O
H
MeO
N
OMe
EtO2C
R'
35, 36
O
c, d
MeO C
2
HO
a, b
OMe
EtO2C
O
EtO2C
MeO C
NH
2
2
R'
N
H
a
H
20
25
26
34
37
39
CF
3
dr = 12:1
H NOC
2
H NOC
2
O
H
O
N
N
b
e
O
N
N
EtO2C
N
NH2
H
H
Cl
38
H
27
dr = 10:1
O
35 R' =
36 R'=
N
N
CF
3
H
H
Cl
N
same as
above
EtO2C
O
NH2
EtO2C
Scheme 8. Reagents and conditions: (a) HATU, i-Pr2NEt, 35 or 36,
CH2Cl2, rt, 6 h, 70–85%; (b) i—LiOH, MeOH, H2O, 12 h; ii—EDCI,
HOBT, Et3N, CH2Cl2, 3 h, then add 2 M NH3 in i-PrOH, 3 h, 80–90%.
H
21
28
O
O
dr = 2:1
Scheme 5. Reagents and conditions: (a) MeOH, HC(OMe)3, Amber-
lyst 15, reflux, 3 h; (b) NaOEt, EtOH, reflux, 12 h, 70%, two steps; (c)
acetone, Amberlyst 15, reflux, 3 h: (d) MeONH3Cl, Et3N, EtOH,
(90%, two steps); (e) Raney nickel, H2 (1 atm), EtOH, 92%.
corresponding acid and then converted into the primary
amide 38 to give the aryl piperazine series of inhibitors.
Similarly, amine 34 can was also acylated with aryl ether
acid 36 and further converted into primary amide 39 to
give the aryl ether series of inhibitors.
analog giving a ratio of only 2:1 favoring the trans
isomer.
Both series of inhibitors were evaluated in both human
and mouse 11b-HSD1 and 11b-HSD2 enzymatic as-
says.14 Cellular 11b-HSD1 inhibition was measured in
human embryonic kidney (HEK) cells that overexpress
the enzyme.14 The in vitro metabolic stability of these
compounds was determined in mouse liver microsome
incubation assays. The data for the aryl piperazines
38–47 are summarized in Table 1.
The oxa-adamantane was synthesized from the known
di-ketone 29 (Scheme 6).11 Reduction of 29 followed
by acid catalyzed removal of dioxolane gave a stable
hemiketal 30 which was converted into amine through
hydrogenation of in situ generated imine giving amine
31 in 5:1 ratio.
The known bicyclo[2.2.2]octane acid 33 was synthesized
from commercially available 32 following literature pro-
cedures.12 Curtius rearrangement followed by debenzy-
lation gave amine 34 in good overall yield (Scheme 7).
Several general observations can be made upon exami-
nation of the data. Nearly all of the carbocyclic adaman-
tane replacements gave potent and selective aryl
piperazine inhibitors against human 11b-HSD1 with
compounds 38 and 41 reaching 20 nM IC50 (Table 1).
In addition, a few of these compounds are very metabol-
ically stable (43, 45–47). With these potent inhibitors
featuring structurally different carbocycle head groups,
we are able to expand our understanding of human
11b-HSD1 SAR. Moreover, the metabolically stable
compounds can be used in vivo studies. Contrary to
the human enzyme, it was much more difficult to obtain
active molecules against mouse 11b-HSD1. For exam-
ple, the cyclooctane compound 40 and bicyclo[5.1.0]oc-
tane amide 41 are both potent against the human
enzyme but much weaker against the mouse enzyme.
Compound 40 is metabolically unstable. Both acid (43
and 46) or primary amide polar head groups are tolerat-
ed by the human enzyme, but the mouse enzyme prefers
primary amides over acid groups (46 vs 47). It is interest-
ing to note that the geometrical isomers 44 and 45 not
only differ in enzymatic activities, but they also showed
significant differences in metabolic stability. The mouse
11b-HSD1 active compound 47 has a [3.3.1] carbocyclic
group that closely mimics the topology and polar group
orientations of the original adamantane carboxamide
lead 1.
Scheme 8 shows the reaction sequence that was used for
the completion of the 11b-HSD1 inhibitors. Amine 34
was acylated with aryl piperazine acid 3513 to give an
intermediate ester 37. The ester was hydrolyzed to the
H
O
O
c
a, b
O
NH2
HO
HO
O
O
O
O
29
30
31 dr = 5:1
Scheme 6. Reagents and conditions: (a) NaBH4, MeOH, rt, 3 h, 71%;
(b) 6 N HCl, dioxane, 70 °C, 48 h, 57%; (c) H2, 7 N NH3/MeOH, 5%
Pd/C, 12 h, 98%.
O
CO2Me
a, b
MeO2C
CO2H
MeO2C
32
33
O
MeO2C
NH2
34
The in vitro biological data for the aryl ether series of
inhibitors are presented in Table 2. Unlike the aryl
piperazine inhibitors, several compounds in Table 2
Scheme 7. Reagents and conditions: (a) DPPA, Et3N, BnOH, tol,
reflux, 12 h, 80%; (b) H2, Pd(OH)2/C, MeOH, 3 h, 99%.

V. S. C. Yeh et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5408–5413
5411
Table 1. In vitro inhibition and metabolic stability data for aryl piperazine inhibitors 38–47
CF
3
O
N
N
N
R
a
IC50 (nM)
Compound
R
Microsomal stability (% remaining)b
h-HSD1/h-HSD2
66/>30,000
m-HSD1/m-HSD2
h-HSD1 HEK
219
NC
40
4780/>100,000
8
N
H
H
H
H
41
42
24/>30,000
269/ND
119/>100,000
>10,000/ND
185
ND
NDc
ND
H NOC
2
NH
H2NOC
N
H
HN
H
43
44
97/>30,000
>10,000/>10,000
10,000/>30,000
75
97
17
H
H
HO2C
HN
H2NOC
164/>30,000
1000
H
H
H
H
H NOC
2
45
46
47
38
88/>30,000
44/>100,000
62/>100,000
23/90,000
4000/>30,000
1150/15,000
62/85,000
73
606
65
75
N
H
HO2C
91
N
H
H
H
H NOC
2
85
N
H
H
H2NOC
2000/>100,000
442
ND
N
H
a Values are means of two experiments.
b % remaining after a 30-min incubation with mouse liver microsomes.
c Not determined.
achieved excellent potency and selectivity for both hu-
man and mouse 11b-HSD1 enzymes. Compounds 39,
51, 53, and 55 are highlighted for their potency with
compound 53 reaching IC50 of 5 nM. A number of com-
pounds in Table 2 also feature excellent metabolic stabil-
ity. In this series, acid head group is well tolerated in
both species (50 and 52). 50 is also highly metabolically
stable and it might offer different in vivo profiles than
the primary carboxamides. Bicyclo[3.3.1]nonane 51 is
particularly interesting since it is both potent and meta-
bolically stable, and it contains a more polar heteroaryl
side chain (described in the preceding communication)1
that might offer other desirable characteristics such as
increased water solubility. Oxabicyclic inhibitors such
as 54 and 55 are also very potent and selective. More-
over, oxygen substitution in the bridge ring provided
significant improvement in metabolic stability as com-
pared to the all carbon analog (53 vs 54). Compound
39, which features a rigid bicycle[2.2.2]octane head
group, also shows excellent potency and metabolic sta-
bility. It is interesting to note that although compounds
such as 53 and 39 do not differ significantly in physical
properties, they showed large differences in their cellular
activities (HEK, 8 nM vs 450 nM) and metabolic stabil-
ities (21% vs 85% remaining). We examined compounds
55 and 39 in our pharmacodynamic assay (Table 3).14
The inhibition of 11b-HSD1 was measured ex vivo in
liver, epidydimal fat pad, and brain of DIO mice at 1,

5412
V. S. C. Yeh et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5408–5413
Table 2. In vitro inhibition and metabolic stability data for aryl ether inhibitors 39, 48–55
O
O
R
Cl
Microsomal stability (% remaining)b
a
IC50 (nM)
Compound
R
h-HSD1/h-HSD2
54/>100,000
m-HSD1/m-HSD2
h-HSD1 HEK
637
NC
48
49
255/>100,000
>10,000/ND
0.1
N
H
H
H
H
587/ND
ND
80
ND
EtO2C
NH
H
H
HO2C
50
22/16,000
32/1820
90
89
N
H
H
H
H2NOC
HO2C
51c
11/>100,000
28/>100,000
22
N
H
H
52
53
149/ND
164/ND
ND
ND
21
N
H
H
H
H NOC
2
5/>100,000
3/100,000
8
N
H
H
H
N
H NOC
2
54
55
25/>100,000
15/70,000
23/>100,000
24/>100,000
2400
199
88
98
H
H
O
H
N
HO
O
H
H2NOC
39
13/100,000
28/>100,000
450
85
N
H
a Values are means of two experiments.
b % remaining after a 30-min incubation with mouse liver microsomes.
c Compound 51 has the following acyl side chain.
O
O
N
R
CN
Table 3. Ex vivo pharmacodynamic dataa
help us establish the effect of the ability of these com-
pounds to cross the blood–brain barrier. Compound
55 displayed 43% inhibition of the target enzyme in liver
at 7 h and none at 16 h. Compound 39 showed robust
inhibition in liver and brain at 16 h with weaker activity
in fat.
Compound % inhibition in % inhibition in % inhibition in
liver 7 h/16 h
fat 7 h/16 h
brain 7 h/16 h
55
39
43/0
80/70
ND
40/20
ND
60/72
a See Ref. 1 for assay details.
In conclusion, a number of structurally novel and meta-
bolically stable adamantane replacements have been
indentified. Several of these bridged carbocycles and het-
erocycles showed good potency against both human and
mouse 11b-HSD1 and excellent selectivity against 11b-
HSD2 in both species in the aryl ether inhibitor series.
7 and 16 h postdose. We hypothesize that long acting
compounds would allow sufficient coverage in BID
dosing scheme in long-term efficacy studies. Therefore,
Table 3 highlights the data for the longer time points.
The inhibition of 11b-HSD1 was measured in brain to

V. S. C. Yeh et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5408–5413
5413
4. Brown, H. C.; Negishi, E. J. Am. Chem. Soc. 1969, 91,
1224.
Compound 39 showed significant 11b-HSD1 inhibition
in liver, fat, and brain in ex vivo assay.
5. For reviews on ring closing metathesis: (a) Grubbs, R. H.;
Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446; (b)
Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 2073.
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M. A.; Ye, T. In Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds; Wiley: New York,
1997; (c) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998,
98, 911.
Acknowledgment
We thank Drs. John Lynch and Gang Liu for helpful
suggestions on the manuscript.
7. Marchand, A. P.; Kumar, V. S.; Hariprakasha, H. K.
J. Org. Chem. 2001, 66, 2072.
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