Bis-aryl triazoles as selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1

Article abstract of DOI:10.1016/j.bmcl.2008.04.010

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

Full text of DOI:10.1016/j.bmcl.2008.04.010

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 2799–2804
Bis-aryl triazoles as selective inhibitors
of 11b-hydroxysteroid dehydrogenase type 1
Susan D. Aster,a,* Donald W. Graham,a Divya Kharbanda,a Gool Patel,a
Mitree Ponpipom,a Gina M. Santorelli,a Michael J. Szymonifka,a Steven S. Mundt,b
Kashmira Shah,b Marty S. Springer,b Rolf Thieringer,b Anne Hermanowski-Vosatka,b
Samuel D. Wright,b Jianying Xiao,b Hratch Zokianb and James M. Balkoveca
aDepartment of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Cardiovascular Disease, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
Received 14 February 2008; revised 2 April 2008; accepted 2 April 2008
Available online 9 April 2008
Abstract—3-Aryl-5-phenyl-(1,2,4)-triazoles were identified as selective inhibitors of 11b-hydroxysteroid dehydrogenase type 1 (11b-
HSD1). They are active in both in vitro and 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 type 1 (11b-HSD1)
resides in the endoplasmic reticulum and catalyzes the
conversion of cortisone to the metabolically active glu-
cocorticoid cortisol1 (Scheme 1).
Elevated levels of cortisol can cause visceral adiposity,
diabetes, dyslipidemia and hypertension collectively
known as Metabolic Syndrome which can greatly in-
crease the incidence of cardiovascular disease.2 The
Scheme 1. Interconversion of cortisone and cortisol.
structurally related enzyme 11b-hydroxysteroid dehy-
drogenase type 2 (11b-HSD2) protects the mineralocor-
ticoid receptor from activation by cortisol by catalyzing
Published work from our laboratories identified ada-
the reverse reaction of cortisol to cortisone.3 It has been
mantyl triazole 1 (Fig. 1) as a potent and selective inhib-
shown that 11b-HSD1 knockout mice resist metabolic
itor of both mouse and human 11b-HSD1 enzymes7;
syndrome, while overexpression of 11b-HSD1 in mouse
pharmacodynamic (PD) assays indicated good in vivo
adipose tissue leads to a metabolic syndrome-like phe-
activity as well.8
notype.4 Since inhibition of 11b-HSD2 is known to re-
sult in hypokalemia, sodium retention and
hypertension5 the discovery of a selective 11b-HSD1
inhibitor could lead to an effective treatment for meta-
bolic syndrome.6
Further investigation in our laboratory led us to explore
the SAR of relatively simple, substituted bis-phenyl tri-
Keywords: 11b-Hydroxysteroid dehydrogenase; Metabolic syndrome ;
Bis-aryl triazoles.
azoles. Schemes 2–4 below show thethree different meth-
ods that were used to prepare these triazoles.
*
Corresponding author. Tel.: +732 +1 732 594 5337; fax: +732 +1 732
594 3007; e-mail: susan_aster@merck.com
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.04.010

2800
S. D. Aster et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2799–2804
activity. The poor potency of compounds lacking any
substituents in ring 2 (16–18) suggests that perhaps
ortho-substitution forces the phenyl out of the plane of
the triazole and helps it to more efficiently fill a hydro-
phobic pocket in the enzyme active site.
We next explored the effect of including non-halogens in
ring 2 of the bis-aryl triazoles. Data for these com-
pounds are shown in Table 2.
Figure 1. Adamantyl-phenyl triazole.
Data for selected compounds are shown in Table 1.
These compounds were tested against both human and
mouse 11b-HSD1 and 11b-HSD2 and the table includes
data from PD assays as well. IC50 values for the mouse
and human 11b-HSD2 counterscreen were >4000 nM
for all compounds.
SAR data from compounds 22–25 indicate that good
potency is maintained when the ring 2 phenyl is substi-
tuted at the para position with a 4 or 5 carbon chain,
with or without a sulfonyl group, and the ortho position
is occupied by a methyl or chloro group. Compound 26
shows that potency in the PD assay begins to drop when
the 5-carbon chain is combined with a lack of substitu-
tion at the ortho position. A further dropoff in activity is
observed (28 and 29), when there is no substitution on
ring 1. Finally, 30–32 show that the strongly electron-
withdrawing nitro and methylsulfonyl groups in the
ortho or para position substantially lower activity in
the mouse.
SAR data from compounds 1–11 show that ortho-Cl,
-Br and -CF3 in both rings is needed for good activity.
Comparison of compounds 3 and 12 reveals that
ortho-F appears to lower the potency. This is seen again
with compounds 13–15. Halogen substitution in the
meta or para position (compounds 19–21) also lowers
Scheme 2. Method A for the preparation of bis-phenyl triazoles.
Scheme 3. Method B for the preparation of bis-phenyl triazoles.
Scheme 4. Method C for the preparation of bis-phenyl triazoles.

S. D. Aster et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2799–2804
Table 1. SAR of halogen and CF3-substituted bis-phenyl triazoles
2801
Compound
R1
R2
IC50 (nM)
PD (% inhibition)
16 h
hHSD1
mHSD1
4 h
1
2
o-CF3
o-CF3
o-CF3
o-Cl
o-OCF3
o-Cl
1.3
3.1
2.6
2
4.5
8.6
42
79
70
70
67
67
65
56
46
43
34
27
—
—
—
—
11
À3
—
—
—
—
2
4
3
o-Cl, p-F
o-Br
o-Cl
5
4
12
22
À1
À6
0
5
o-Cl
2.9
21
6
2,4-di-Cl
o-CF3
o-CF3
o-CF3
o-Cl
2,4-di-Cl
o-Br
89
8
7
1
0
8
o-CF3
2,4-di-Cl
o-Cl,p-F
2,3-di-CF3
o-F,p-Cl
o-F
.98
1.3
5.8
3.6
15
7.1
11
3
9
0
10
11
12
13
14
15
16
17
18
19
20
21
71
22
2
o-CF3
o-CF3
2,4-di-Cl
o-CF3
o-Cl
0
100
180
260
140
120
190
850
1300
410
1500
—
—
—
—
4
20
32
2,3-di-F
2-F, 4-CF3
H
88
27
o-CF3
o-Cl
H
43
90
—
—
—
—
—
2,4-di-Cl
o-CF3
o-Cl
H
3,5-di-Cl
3,4-di-Cl
p-Cl
89
200
630
2,4-di-Cl
Table 2. SAR of non-halogen (ring 2) with halogen and CF3-substituted (ring 1) bis-phenyl triazoles
Compound
R1
R2
IC50 (nM)
PD (% inhibition)
hHSD1
28
mHSD1
6.4
4 h
16 h
22
o-CF3
86
76
73
15
3
23
24
o-CF3
o-CF3
34
28
11
8.4
11
25
26
27
28
29
30
31
32
o-CF3
o-CF3
o-Cl
2-Me; 4-n-C 4H9
4-n-C 5H11
4-n-C 5H11
4-n-C 4H9
4-n-C 5H11
o-NO2
<1
5.2
7.7
260
250
13
<1
2.9
76
53
38
25
9
À5
5
10
68
3
H
—
—
—
—
—
H
54
2,4-di-Cl
o-Cl
o-Cl
140
1500
3000
—
—
—
o-SO2Me
p-SO2Me
38
50

2802
S. D. Aster et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2799–2804
Scheme 5. Method D for the preparation of indole-phenyl triazoles.
Scheme 6. Method E for the preparation of indole-phenyl triazoles.
Table 3. SAR of indole-phenyl triazoles
Compound
R1
R2
IC50 (nM)
PD (% inhibition)
4 h 16 h
hHSD1
3.9
mHSD1
33
p-OH
6.6
75
À8
34
35
o-Cl
.98
1.2
1.3
66
52
4
8
o-CF3
.98
36
37
H
H
12
91
9
0
963
346
—
—

S. D. Aster et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2799–2804
Table 4. SAR of naphthyl-phenyl triazoles
2803
Compound
R1
R2
IC50 (nM)
PD (% inhibition)
4 h 16 h
hHSD1
<1
mHSD1
<1
38
o-CF3
70
77
37
35
24
15
14
14
13
10
7
74
31
0
39
40
41
42
43
44
45
46
47
48
49
o-CF3
o-CF3
o-CF3
o-CF3
o-CF3
o-CF3
o-CF3
o-CF3
o-CF3
o-SO2Me
o-CF3
<1
4.3
26
<1
2.8
15
5
1.4
2.3
5
9
10
À4
3
2.7
20
89
19
0
2.9
2.3
1.9
4.6
9.8
2.3
1.9
46
4
À5
0
0
—

2804
S. D. Aster et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2799–2804
We also investigated the effect of substituting indole for
phenyl on the western side of the triazole. These com-
pounds were prepared by Method D (Scheme 5) or
Method E, (Scheme 6). Data for compounds in this ser-
ies are presented in Table 3.
References and notes
1. For recent reviews see: Tomlinson, J. W.; Walker, E. A.;
Bujalska, I. J.; Draper, N.; Lavery, G. G.; Cooper, M. S.;
Hewison, M.; Stewart, P. M. Endocr. Rev. 2004, 25, 831;
Seckl, J. R.; Walker, B. R. Trends Endocrinol. Metab. 2004,
15, 418; Walker, E. A.; Stewart, P. M. Trends Endocrinol.
Metab. 2003, 14, 334; Walker, B. R.; Seckl, J. R. Expert
Opin. Ther. Targets 2003, 7, 771.
2. (a) Reaven, G. Circulation 2002, 106, 286; (b) Seckl, J. R.;
Walker, B. R. Trends Endocrinol. Metab. 2004, 15, 418,
(and references therein).
3. (a) Kotelevtsev, Y. V.; Brown, R. W.; Fleming, S.;
Edwards, C. R.; Seckl, R. J.; Mullins, J. J. J. Clin. Invest.
1999, 103, 683; (b) Wilson, R. C.; Harbison, M. D.;
Krozowski, Z. S.; Funder, J. W.; Shackleton, C. H.;
Hanauske-Abel, H. M.; Wei, J. Q.; Hertecant, J.; Moran,
A.; Neiberger, I. E. Clin. Endocrinol. Metab. 1995, 80,
3145; (c) Monder, C.; Stewart, P. M.; Lakshimi, V.;
Valentino, R.; Burt, D.; Edwards, C. R. Endocrinolgy
1989, 125, 1046.
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294, 2166; (b) Masuzaki, H.; Yamamoto, H.; Kenyon, C. J.;
Elmquist, J. K.; Morton, N. M.; Paterson, J. M.; Shinyama,
H.; Sharp, M. G. F.; Fleming, S.; Mullins, J. J.; Seckl, R. J.;
Flier, F. S. J. Clin. Invest. 2003, 112, 83; (c) Paterson, J. M.;
Morton, N. M.; Fievet, C.; Kenyon, C. J.; Holmes, M. C.;
Staels, B.; Seckl, R. J.; Mullins, J. J. J. Proc. Natl. Acad.
Sci. 2004, 101, 7088.
The N-methyl indole series (33–35 compared with 36–
37) reiterates what was observed with the bis-phenyl
compounds in that substitution on the phenyl ring is
needed for potency. The indoles differ in that a para sub-
stituent (p-OH in 33) rather than just the ortho, confers
very good activity, a phenomenon which was observed
with an earlier set of analogs we examined. In addition,
the potency is substantially lowered if connection to the
triazole is on C5 of the indole (37).
The final area that we explored was replacing the indole
group with a naphthylene. These triazoles were prepared
using Methods A, B and C (Schemes 2–4). Table 4 dis-
plays the observed SAR for these compounds.
The potency of compound 38, the 7-chloro-1-methoxy
naphthyl triazole surpasses all the others in the bis-aryl
series with its good PD activity extending out to 16 h but
seems to have rather specific requirements for maintain-
ing this activity. The 16 h potency is reduced somewhat
(39) when the chloro substituent is absent. A much lar-
ger drop in mouse PD activity is seen with the chloro at
the 4-position (47), when o-SO2Me replaces the o-CF3
on the phenyl ring (48) or when the methoxy is replaced
by a hydroxyl group (45); human potency is also lower
with (45). PD potency is generally lower when just a sin-
gle substituent (1-fluoro, 1-N-methylamino, 7-methyl or
3-chloro) is present on the naphthyl ring. Finally, mouse
activity drops significantly and is reflected in poor PD as
well if the connection to the triazole is on C1 of the
naphthyl (49).
5. For a review see: White, P. C.; Mune, T.; Agarwal, A. K.
Endocr. Rev. 1997, 18, 135.
6. Hermanowski-Vosatka, A.; Balkovec, J. M.; Cheng, K.;
Chen, H. Y.; Hernandez, M.; Koo, G. C.; LeGrand, C.
B.; Li, Z.; Metzger, J. M.; Mundt, S. S.; Noonan, H.;
Nunes, C. N.; Olson, S. H.; Pikounis, B.; Ren, N.;
Robertson, N.; Schaeffer, J. M.; Shah, K.; Springer, M.;
Strack, A. M.; Strowski, M.; Wu, K.; Wu, T.; Xiao, J.;
Zhang, B. B.; Wright, S. D.; Thieringer, R. J. Exp. Med.
2005, 202, 517.
7. Olson, S. H.; Aster, S. D.; Brown, K.; Carbin, L.; Graham,
D. W.; Hermanowski-Vosatka, A.; LeGrand, C. B.;
Mundt, S. S.; Robbins, M.; Schaeffer, J. M.; Slossberg, L.
H.; Szymonifka, M. J.; Thieringer, R.; Wright, S. D.;
Balkovec, J. M. Bioorg. Med. Lett. 2005, 12, 4359.
8. For details of enzymatic assays see Ref. 6. The pharmaco-
dynamic (PD) assay was performed as follows. The test
compound was dosed orally at 10 mg/kg, and after a
In summary, we have identified several new classes of
potent and selective mouse and human 11b-HSD1
inhibitors. Potency of relatively simple bis-phenyl tria-
zoles has been enhanced by the inclusion of various o-
halogens and the o-CF3 group. Potency can be main-
tained by incorporating a 4- or 5-carbon chain in the
4-position. Good activity is observed with an N-methyl
indole replacing one of phenyls and para substitution
on the 2nd phenyl ring is well tolerated. Finally, ex-
tended PD potency out to 16 h is seen with a 7-chloro-
1-methoxy naphthyl group replacing one of the phenyls.
3
prescribed time interval, H-cortisone was injected intrave-
nously via the tail vein. After 2 min, blood was collected by
cardiac puncture. Steroids were extracted from the serum
and analyzed by HPLC. The relative levels of H-cortisone
3
and 3H-cortisol were measured and a percent inhibition was
calculated.