4-Methyl-5-phenyl triazoles as selective inhibitors of 11β-hydroxysteroid dehydrogenase type I

Article abstract of DOI:10.1016/j.bmcl.2008.04.013

4-Methyl-5-phenyl-(1,2,4)-triazoles were identified as selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). They were active in vitro and in an in vivo mouse pharmacodynamic (PD) model. The synthesis and structure activity relations

Full text of DOI:10.1016/j.bmcl.2008.04.013

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 3405–3411
4-Methyl-5-phenyl triazoles as selective inhibitors
of 11b-hydroxysteroid dehydrogenase type I
Yuping Zhu,a,* Steven H. Olson,a Anne Hermanowski-Vosatka,b Steven Mundt,b
Kashmira Shah,b Marty Springer,b Rolf Thieringer,b Samuel Wright,b
Jianying Xiao,b Hratch Zokianb and James M. Balkoveca
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Cardiovascular Disease, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 30 January 2008; revised 4 April 2008; accepted 7 April 2008
Available online 10 April 2008
Abstract—4-Methyl-5-phenyl-(1,2,4)-triazoles were identified as selective inhibitors of 11b-hydroxysteroid dehydrogenase type 1
(11b-HSD1). They were active in vitro and in an in vivo mouse pharmacodynamic (PD) model. The synthesis and structure activity
relationships are presented.
Ó 2008 Elsevier Ltd. All rights reserved.
11b-Hydroxysteroid dehydrogenase enzymes (11b-
HSD) interconvert cortisol and cortisone in man, and
corticosterone and 11-dehydrocorticosterone in rodents.
The type I isoform (11b-HSD1), which is located in the
membranes of the endoplasmic reticulum, converts
11-keto metabolites into active glucocorticoids in the
presence of NADPH.1 The type II isoform (11b-
HSD2) utilizes NAD2 to metabolize glucocorticoids to
11-keto compounds which possess low affinity for gluco-
corticoid and mineralocorticoid receptors3 (Scheme 1).
The discovery and development of selective 11b-HSD1
inhibitors is an important area of academic and pharma-
ceutical research.8
Previously, we identified adamantyl triazole 1 as a po-
tent and selective inhibitor of 11b-HSD1 by high-
throughput screening. It was determined to have an
IC50 versus human 11b-HSD1 of 7.8 nM (98 nM for
mouse) using an SPA-based assay.9 In a human 11b-
HSD2 counterscreen, the compound had an IC50 of
>3000 nM (>10,000 nM for mouse). We also described
phenyl analog 2 which possesses similar hydrophobicity
and mouse 11b-HSD1 activity (109 nM). The mouse
pharmacodynamic activity of 2, which measures the in
vivo activity of the inhibitor,9 is significantly improved,
suggesting improved pharmacokinetics for this analog10
(Table 1).
Glucocorticoids are important regulators of glucose and
lipid homeostasis, acting largely via intracellular gluco-
corticoid receptors in the liver, adipose tissue, and mus-
cle. Glucocorticoid excess, epitomized by Cushing’s
syndrome in humans, leads to insulin resistance/type 2
diabetes, dyslipidemia and a redistribution of fat to vis-
ceral depots associated with increased cardiovascular
risk.4,5 Therefore, selective inhibition of the 11b-HSD1
enzyme may lead to an effective treatment for metabolic
syndrome. The selectivity over 11b-HSD2 is very impor-
tant since inhibition of 11b-HSD2 is known to result in
sodium retention, hypokalemia, and hypertension.6,7
Keywords: 11b-HSD1;
syndrome.
4-Methyl-5-phenyl triazole; Metabolic
*
Corresponding author. Tel.: +1 732 594 0017; fax: +1 732 594
3007; e-mail: yuping_zhu@merck.com
Scheme 1. Enzymatic interconversion of cortisone and cortisol.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.04.013

3406
Y. Zhu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3405–3411
Table 1. SAR of N-alkyl-substituted adamantyl triazoles10
Compound
IC50 (nM)
Mouse
pharmacodynamic assay
(% inhibition)a
Human 11b-HSD1
Mouse 11b-HSD1
Human 11b-HSD2
Mouse 11b-HSD2
1 h (%)
4 h (%)
1
2
7.8
37
98
109
>3000
>4000
>10,000
>4000
31
85
21
47
a % Inhibition of the conversion of [3H]-cortisone to [3H]-cortisol after a single oral dose of compound at 10 mg/kg.
Triazole 4 and its analogs were prepared from the corre-
sponding methyl amide (54) and acylhydrazide (55) in a
one pot reaction. The amides were converted to methyl
imino ethers with one equivalent of neat methyl triflate
followed by addition of an acylhydrazide in the presence
of base (Scheme 2). A number of phenyl substituents
were prepared and evaluated (Table 3). For simple sub-
stitution, we found that –OH, –OCF3, –Cl, and –CF3
gave similar human 11b-HSD1 activity as triazole 4,
but the mouse 11b-HSD1 activity improved signifi-
Through SAR studies that focused on the left side of tri-
azole 1, we identified phenyl cyclobutyl triazole 3 as a
more potent inhibitor of 11b-HSD1 (IC50 vs human
11b-HSD1 1.3 nM; 13.5 nM for the mouse enzyme).11
Compared to 3, the 5-phenyl analog 4 had poorer phar-
macodynamic activity which we believe resulted from its
weaker mouse 11b-HSD1 activity (52 nM). Our previ-
ous studies in adamantyl triazoles series showed that
the phenyl analog, which has comparable mouse 11b-
HSD1 activity, also had a significantly improved phar-
macodynamic activity.10 Therefore in order to improve
the in vivo pharmacodynamic activities in this series,
we explored the SAR of the phenyl group on the
right-hand side of the triazole (Table 2).
Table 3. SAR of small substituent group substitutions of phenyl
cyclobutyl triazoles
Compound R =
11b-HSD1
IC50 (nM)
Mouse
pharmacodynamic
assay
a
Human Mouse
(% inhibition)b
5
6
p-OH
0.34
1.8
1
19
17
17
10
À2
—
27
44
—
14
73
12
—
—
—
—
63
—
1
o-OH
À2
—
64
59
—
20
86
24
—
—
—
—
73
—
9
7
m-OH
p-OCF3
o-OCF3
m-OCF3
p-Cl
19
8
13
6.9
4.1
36
9
2.3
2.2
2.7
0.28
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
43
o-Cl
3.5
34
m-Cl
p-F
1.5
2
101
21
o-F
m-F
2.2
9.3
2
163
26
p-CF3
o-CF3
p-I
4
Table 2. SAR of phenyl cyclobutyl triazoles
3.8
5
8.2
21
Compound
11b-HSD1
IC50 (nM)
Mouse pharmacodynamic
b
assay
o-CH3
o-OCH3
2,4-di-Cl
3-F, 4-OH
3-F, 4-OCH3
a
2.7
1
7.8
13
28
—
3
12
—
6
Human
Mouse
1 h (%)
4 h (%)
2
61
3
4
1.3
1.7
13.5
52
91
47
77
29
3
42
10
95
À1
95
4-Cyclopropyloxy 10
2.2
a The human and mouse 11b-HSD2 IC50s were >4000 nM for all
compounds.
b % Inhibition of the conversion of [3H]-cortisone to [3H]-cortisol after
a single oral dose of the test compound at 10 mg/kg.
a The human and mouse 11b-HSD2 IC50s were >4000 nM for all
compounds.
b % Inhibition of the conversion of [3H]-cortisone to [3H]-cortisol after
oral dosing with compound at 10 mg/kg.
Scheme 2. Synthesis of phenyl cyclobutyl triazoles.

Y. Zhu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3405–3411
3407
cantly. For the same substituent, the ortho-position gave
the greatest potency in the mouse while meta-substitu-
tion proved to be the worst. The o-Cl and the 4-cyclo-
propyloxy analogs were found to be the most potent
compounds in this series.
a very good yield (79%) of imidazole analog 32
(Scheme 4).13
The SAR of heterocyclic substitution was also explored.
The thiazole analog was very potent versus mouse 11b-
HSD1 (IC50 3.1 nM) although human 11b-HSD1 activity
dropped to 44 nM. This analog also had good pharmaco-
dynamic activity (92% at 1 h; 67% at 4 h). The pyrrole ana-
log had excellent activity versus both human and mouse
11b-HSD1 (3 nM vs human, 5.4 nM vs mouse). Unfortu-
nately, the pharmacodynamic activity of this analog was
relatively poor (41% at 1 h, 28% at 4 h) (Table 5).
We also explored a number of biphenyl triazole analogs.
For biphenyl substitution, mouse 11b-HSD1 activity in-
creased, however, human 11b-HSD1 activity decreased.
Among those substituents, the p-Ph analog gave the high-
est pharmacodynamic activity (86% at 1 h; 90% at 4 h)
(Table 4).
The synthesis of compounds 26–27 and 29–31 was similar
to that shown in Scheme 1. However, the same route did
not apply to the synthesis of compound 28. Analog 28
was obtained in 95% yield through Suzuki coupling
(Scheme 3).
Since both o-Cl and p-Ph substitutions improved po-
tency and pharmacodynamic activity, analog 35 which
is the combination of o-Cl and p-Ph was prepared. This
analog showed excellent potency versus both human
and mouse 11b-HSD1 (1 nM for human, 1.4 nM for
mouse). It is not surprising that we found the pharmaco-
dynamic activity of 35 was much improved over the two
precursors (99% at 4 h, 85% at 16 h). Unfortunately, this
analog was a full and potent Pregnane X Receptor
12
Heterocyclic substitution on the phenyl triazole was
accomplished via a copper mediated coupling of the
aryl iodide. Using Cu (I) triflate as the catalyst gave
Table 4. SAR of large group substitutions on methyl phenyl cyclobutyl triazoles
Mouse pharmacodynamic assayb
a
Compound
R =
11b-HSD1 IC50 (nM)
Human
11
4.3
Mouse
1 h (%)
4 h (%)
26
27
28
29
30
31
p-Ph
m-Ph
4
56
86
À2
—
20
—
—
90
À2
—
À4
—
—
p-4-F-Ph
p-Bn
11
68
14
26
9.1
18
p-tert-Butyl
p-OPh
1.8
3.7
a The human and mouse 11b-HSD2 IC50s were >4000 nM for all compounds.
b % Inhibition of the conversion of [3H]-cortisone to [3H]-cortisol after oral dosing with compound at 10 mg/kg.
Scheme 3. Synthesis of 28.
Scheme 4. Synthesis of 32.

3408
Y. Zhu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3405–3411
Table 5. SAR of heterocyclic substitution on methyl phenyl cyclobutyl triazoles
Mouse pharmacodynamic assayb
a
Compound
R =
11b-HSD1 IC50 (nM)
Human Mouse
1 h (%)
4 h (%)
32
33
34
3.5
3
46
79
44
N
N
N
5.4
41
92
28
67
S
44
3.1
N
a The human and mouse 11b-HSD2 IC50s were >4000 nM for all compounds.
b % Inhibition of the conversion of [3H]-cortisone to [3H]-cortisol after oral dosing with compound at 10 mg/kg.
(PXR) agonist (EC50 1.7 lM) suggesting cytochrome
P450 induction might be an issue at pharmacologically
relevant exposures.
Molecular modeling suggested that introduction of po-
lar groups at the end of the molecule could reduce hu-
man PXR activity by destabilizing interactions in the
hydrophobic area of the ligand binding pocket.14 There-
fore, a series of analogs with heterocyclic substitution
was prepared. The pyridine analogs of 35 were prepared
as shown in Scheme 5. The imidazole analogs of 35 how-
ever, could not be synthesized utilizing the same chemis-
try. To solve this problem, we prepared the boronic acid
Scheme 5. Synthesis of 35.
Scheme 6. Synthesis of heterocycle substituted methyl o-Cl phenyl cyclobutyl triazoles.

Y. Zhu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3405–3411
3409
Table 6. SAR of heterocyclic substitution on methyl ortho-chlorophenyl cyclobutyl triazoles
Compound
R =
11b-HSD1 IC50 (nM)
Mouse
pharmacodynamic
assay (% inhibition)
PXR activity
Human
Mouse
1.3
4 h (%)
16 h (%)
EC50 (lM)
% Activation at 10 lM
36
37
38
39
40
41
1
100
26
3.6
35%
42%
98%
21%
22%
—
N
1
2
39
41
78
—
—
8
7.7
2.4
12
N
N
1
1.4
2.8
9.6
7.2
À5
10
—
—
1
N
N
2.6
6.9
>25
—
N
N
N
N
42
9.8
6
60
7
1.3
13%
N
N
CF3
N
43
44
0.98
3.9
0.96
3.9
58
—
20
—
3.2
—
24%
N
N
S
N
—
O
S O
N
45
46
14
12
9.4
—
—
—
—
7.9
23%
N
N
N
57
—
—

3410
Y. Zhu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3405–3411
Table 7. SAR of sulfone analogsb
a
IC50 (nM)
Compound
R =
Mouse pharmacodynamic
assay (% inhibition)
PXR activity
Human
11b-HSD1
Mouse
11b-HSD1
Human
11b-HSD2
4 h
(%)
16 h
(%)
EC50
(lM)
% Activation
at 10 lM
O
S
47
48
2.1
0.98
75% inh. at 4 lM
71
51
16
>25
À8%
O
S
11
4.7
54% inh. at 4 lM
1
1.7
48%
O
S
49
0.98
1.2
>4000
56
6
0.7
74%
O
O
S
50
0.98
0.98
59% inh. at 4 lM
93
29
25
À31%
O
O
S
51
52
1.7
1.2
>4000
>4000
20
96
À5
>25
>25
2%
O
O
S
O
0.98
0.98
36
À5%
a Mouse 11b-HSD2 IC50s were >4000 nM for all compounds.
b Data also shown in Ref. 14.
intermediate15 to couple with imidazole pieces using
[Cu(OH)TMEDA]2Cl2 as catalyst.16 (see Scheme 6).
In conclusion, a novel class of potent and selective inhib-
itors of mouse and human 11b-HSD1 have been identi-
fied. These analogs showed potent in vivo 11b-HSD1
activity in a mouse pharmacodynamic model. It was
found that small group substitutions at the ortho-posi-
tion and larger group substitutions at the para-position
increase in vivo activity. By introducing polar groups at
the end of molecule, we successfully eliminated PXR
activity while maintaining both in vitro and in vivo
activity. Additional optimization of these lead com-
pounds may eventually lead to a treatment strategy for
metabolic syndrome.
The PXR assay data, in accordance with the modeling
predictions, showed that substitution with a polar group
can reduce the PXR activity. For the pyridine analog,
nitrogen substitutions at the 3- or 4-position had lower
PXR activity (35% and 42% activation at 10 lM) than
the analog with a less exposed nitrogen (2-substitution)
(98% activation at 10 lM). All the imidazole analogs de-
creased the PXR activation to less than 25% at 10 lM.
The docking model suggested that the polarity of the
imidazole and pyridine groups makes them unfavorable
to the highly hydrophobic binding site, thereby reducing
the receptor activation compared to their non-polar par-
ent compound 35 (Table 6).
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3411
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