Bioorganic & Medicinal Chemistry Letters
Substituted phenyl triazoles as selective inhibitors of 11b-Hydroxysteroid
Dehydrogenase Type 1
Wanying Sun a, , Milana Maletic a, Steven S. Mundt b, Kashmira Shah b, Hratch Zokian b, Kathy Lyons c,
⇑
Sherman T. Waddell a, James Balkovec a
a Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
b Department of Cardiovascular Disease, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
c Department of Drug Metabolism, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
3-(Phenylcyclobutyl)-1,2,4-triazoles were identified as inhibitors of 11b-Hydroxysteroid Dehydrogenase
Type 1 (HSD1). They were shown to be active in the mouse in vivo pharmacodynamic model (PD) for
HSD1 but exhibited a potent off-target activation of the Pregnane X Receptor (PXR). SAR studies and syn-
thesis of analogs that led to the discovery of a selective HSD1 inhibitor are described in detail.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 28 October 2010
Revised 27 January 2011
Accepted 28 January 2011
Available online 2 February 2011
Keywords:
11b-Hydroxysteroid Dehydrogenase Type 1
Pregnane X Receptor
Metabolic Syndrome
Glucocorticoids are hormones that play key roles in lipid and
glucose metabolism. At the tissue level, glucocorticoid activity is
regulated by 11b-Hydroxysteroid Dehydrogenase Type 1 (HSD1),
which in vivo converts the inactive glucocorticoid cortisone to
the active glucocorticoid cortisol.1 It has been proposed that an
intracellular excess of glucocorticoids in metabolically active tis-
sues such as liver and adipose causes Metabolic Syndrome, a clus-
ter of health problems including hypertension, obesity, visceral
adiposity, diabetes, and dyslipidemia.2 Therefore, inhibition of
HSD1 might lower the concentration of glucocorticoids in liver
and adipose and thereby lead to a novel treatment for Metabolic
Syndrome. Genetic validation for this target comes from the Seckl
laboratories, where it was shown that 11b-HSD1 knockout mice re-
sist Metabolic Syndrome,3 whereas overexpression of HSD1 in
of HSD1. Progression of the HTS hit 1 to more tractable leads 2–4
has been previously described.6,7 Analog 4 was of particular inter-
est to us since it shows an IC50 for human HSD1 of 11 nM (4 nM for
mouse) using a SPA-based assay and excellent in vivo mouse activ-
ity (86% inhibition at 1 h; 90% inhibition at 4 h) in the pharmaco-
dynamic (PD) assay.8 However, it is
Receptor (PXR) agonist (EC50 1.7
a
potent Pregnane
X
l
M, 90% activation @ 10
l
M),9
raising concerns that at pharmacologically relevant exposures, this
compound might cause induction of Cyp3A4. A detailed SAR paper
describing some of our previous efforts to eliminate this off-target
activity in the biphenyl series has been previously published in this
journal.7 In this Letter we further explore the SAR of the substi-
tuted phenyl class of analogs in order to optimize the potency for
11b-HSD1, improve the PK profile, and reduce PXR activation.
The analogs described in this Letter were prepared from com-
mon intermediates A or B (Scheme 1). The triazole was formed
by cyclization of the activated methyl thioamide with the appro-
priate benzhydrazide to give A or B. Bromo intermediates A were
converted into benzoic acids (5, 14) under standard conditions
and then further elaborated to amide analogs 6–13 and 15 (Table
2). Anilines (16, 22) and amide derivatives (17–24) were prepared
by reduction of nitro group of intermediate B, followed by treat-
ment with the corresponding acid chloride (Table 3). Finally, the
biaryl analogs 25–44 (Table 4) were prepared by Suzuki couplings
of boronic acid (made from A) with the corresponding commer-
cially available bromides.
mouse adipose tissue leads to
a Metabolic Syndrome-like
phenotype.4
A structurally related enzyme, 11b-Hydroxysteroid Dehydroge-
nase Type 2 (HSD2), plays a key protective role in the kidney. This
enzyme, an NADPH-dependent dehydrogenase that converts corti-
sol to cortisone, prevents activation of the mineralocoticoid recep-
tor by cortisol.5 Therefore selectivity for HSD1 inhibition over
inhibition of HSD2 is necessary for a novel and effective treatment
for Metabolic Syndrome.
Our research lab has previously identified a series of triazole
analogs 1–4 (Fig. 1 and Table 1) as potent and selective inhibitors
Docking studies of HSD1 inhibitors with PXR9 suggested that
adding polar groups in place of the distal phenyl ring in 4 would
⇑
Corresponding author.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.