Synthesis and biological evaluation of cyclic sulfamide derivatives as 11β-hydroxysteroid dehydrogenase 1 inhibitors

Article abstract of DOI:10.1021/ml200226x

A new series of cyclic sulfamide derivatives were synthesized and evaluated for their ability to inhibit 11β-HSD1. Among this series, 18e showed good in vitro activity toward human 11β-HSD1, selectivity against 11β-HSD2, microsomal stability, and pharmacokinetic and safety profiles (hERG, CYP, and acute toxicity). Additionally, 18e exhibited good in vivo efficacy in rat and monkey models.

Full text of DOI:10.1021/ml200226x

Letter
pubs.acs.org/acsmedchemlett
Synthesis and Biological Evaluation of Cyclic Sulfamide Derivatives
as 11β-Hydroxysteroid Dehydrogenase 1 Inhibitors
Se Hoan Kim,†,‡,§ Ju Han Bok,†,§ Jae Hong Lee,†,‡ Il Hyang Kim,†,‡ Sung Wook Kwon,†,‡ Gui Bin Lee,†
Seung Kyu Kang,† Ji Seon Park,† Won Hoon Jung,† Hee Yeon Kim,† Sang Dal Rhee,† Sung Hoon Ahn,†
Myung Ae Bae,† Deok Chan Ha,‡ Ki Young Kim,† and Jin Hee Ahn*,†
†Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Yuseong-Gu, Daejeon, 305-600, Korea
‡Department of Chemistry, Korea University, Sungbuk-gu, Seoul 136-701, Korea
S
* Supporting Information
ABSTRACT: A new series of cyclic sulfamide derivatives were synthesized and evaluated for their
ability to inhibit 11β-HSD1. Among this series, 18e showed good in vitro activity toward human
11β-HSD1, selectivity against 11β-HSD2, microsomal stability, and pharmacokinetic and safety
profiles (hERG, CYP, and acute toxicity). Additionally, 18e exhibited good in vivo efficacy in rat
and monkey models.
KEYWORDS: diabetes, antidiabetic agents, 11β-hydroxysteroid dehydrogenase type 1, cyclic sulfamide, adamantyl group
a
Scheme 1
n endoplasmic reticulum-associated enzyme, 11β-hydroxy-
steroid dehydrogenase type 1 (11β-HSD1), acts predom-
A
inantly as an NADPH-dependent reductase in vivo and converts
inactive cortisone to the active glucocorticoid cortisol1 (Figure 1).
Figure 1. Role of 11β-HSD1 between cortisone and cortisol.
The relationship between 11β-HSD1 and type 2 diabetes has
been demonstrated in genetic mouse models. Mice overexpressing
11β-HSD1 in adipose tissues showed metabolic syndrome-like
phenotypes such as central obesity, glucose intolerance, and insulin
resistance.2,3 In contrast, 11β-HSD1-deficient mice were resistant
to the development of high-fat diet-induced obesity and exhibited
improved insulin sensitivity and lipid profiles.4,5 These data suggest
that 11β-HSD1 could be a drug target for the treatment of
metabolic syndrome as well as type 2 diabetes. During the past few
years, a number of small molecule 11β-HSD1 inhibitors have been
reported,6−15 and several candidates including Incyte's compound
are in clinical trials.8
Among the classes of 11β-HSD1 inhibitors, the adamantyl
group is one of the most popular and promising skeletons.9−13
Therefore, we looked for a new 11β-HSD1 inhibitor with an
adamantyl group and found a promising cyclic sulfamide skeleton
with an adamantyl group.
a
Reagents and conditions: (a) tert-Butyl alcohol, CH2Cl2, 0 °C and
then triethylamine, 3-chloropropylamine, 5 °C, 2 h. (b) K2CO3,
DMSO, 0 °C to room temperature, 4 h. (c) Ethyl bromoacetate,
K2CO3, DMF, room temperature, 4 h. (d) LiOH, H2O, MeOH, THF,
room temperature, 3 h. (e) 2-Adamantylamine, EDCI, CH2Cl2, room
temperature, 5 h. (f) 4 M HCl in 1,4-dioxane, room temperature, 4 h.
(f) R-X, K2CO3, DMF, 4 h.
We now report the synthesis of cyclic sulfamide derivatives
with an adamantyl group and their biological evaluation as 11β-
HSD1 inhibitors.
Received: September 16, 2011
Accepted: January 3, 2012
Published: January 17, 2012
© 2012 American Chemical Society
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a
Scheme 2
Table 1. In Vitro Human 11β-HSD1 Inhibitory Activity of
Cyclic Sulfonamide Derivatives
a
Reagents and conditions: (a) 3-Chloropropylamine hydrochloride,
acetonitrile, room temperature to 80 °C, 18 h. (b) Anilines, triethyl-
amine, diethyl ether, room temperature, 4 h. (c) K2CO3, DMSO, 0 °C
to room temperature, 2 h. (d) Ethyl bromoacetate, K2CO3, DMF, room
temperature, 4 h. (d) LiOH, H2O, MeOH, THF, room temperature,
3 h. (f) Oxalyl chloride, 50 °C and then adamantylamines, NaHCO3,
THF, H2O, room temperature, 1 h.
a
Scheme 3
a
IC50 values were determined by GraphPad Prism software. Results are
expressed as means SEMs of triplicate experiments.
2-adamantyl amine to obtain compound 5. Compound 5 was
deprotected by 4 M HCl and alkylated to produce the arylalkyl
cyclic sulfamide derivatives 6.
N-Phenyl cyclic sulfamide derivatives were synthesized
according to Scheme 2. Sulfuryldichloride 7 was coupled with
3-chloropropylamine and anilines to give compound 9, which
was cyclized under basic condition to give 10. Compound 10
was coupled with ethyl bromoacetate to give 11, which was
hydrolyzed and amidated by adamantyl amines to produce final
compound 13.
Analogues bearing substitution on the sulfamide-containing
ring were obtained as shown in Scheme 3. Sulfuryl dichloride 7
was coupled with glycine ethyl ester and anilines to give com-
pound 15, which was N-substituted by alkylation or Mitsunobu
reaction to obtain compound 16. Compound 16 was then
hydrolyzed and coupled with adamantyl amines to produce the
final compound 18.
In vitro inhibition activity of 11β-HSD1 was assessed by
a HTRF cortisol concentration assay. Human and mouse
11β-HSD1 overexpressed cells were incubated with cortisone
and each compound for 3 h. The IC50 values of the compounds
were determined from concentration-dependent inhibition
curves. Carbenoxolone was used as a standard 11β-HSD1
inhibitor.
a
Reagents and conditions: (a) Glycine ethyl ester hydrochloride,
acetonitrile, room temperature to 80 0 °C, 18 h. (b) Anilines,
triethylamine, diethyl ether, room temperature, 4 h. (c) Dihaloalkane,
K2CO3, acetonitrile, reflux, 12 h or diols, PPh3, DIAD, THF room
temperature, 3 h. (d) LiOH, H2O, MeOH, THF, room temperature,
3 h. (e) 4-Aminoadamantane-1-carboxamide hydrochloride, EDCI,
DIPEA, HOBT, DMSO, isopropyl alcohol, room temperature, 5 h.
A series of cyclic sulfamide derivatives were synthesized
according to Schemes 1−3. Chlorosulfonyl isocyanate 1 was re-
acted sequentially with tert-butyl alcohol and chloropropyl-
amine to provide 2, which was cyclized under basic condition
to give Boc-cyclic sulfamide 3. Compound 3 was alkylated
with ethyl bromoacetate to produce compound 4. Alkaline
hydrolysis then provided an acid, which was amidated with
First, Boc-protected cyclic sulfamide derivative with 2-adamantyl
group (5) showed nanomolar inhibitory activity with an IC50
value of 363 nM toward 11β-HSD1. Therefore, we further
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Table 2. In Vitro 11β-HSD1 Inhibitory Activity of Cyclic Sulfonamide Derivatives
a
b
(E)-Adamantylcarboxamide isomer. IC50 values were determined by GraphPad Prism software.
Table 3. In Vitro 11β-HSD1 Inhibitory Activity, Liver Microsomal Stability, and 11β-HSD Inhibition of Cyclic Sulfonamide
Derivatives
a
b
c
(E)-Adamantylcarboxamide isomer. IC50 values were determined by GraphPad Prism software. Liver microsomal stability. Results of ex vivo
11β-HSD1 inhibition are expressed as means SEMs for n = 4 mice per group. **P < 0.01, ***P < 0.001 vs vehicle group.
modified sulfamide scaffold by replacing the Boc group. Instead
with Boc; however, the phenethyl substituent 6b displayed
of Boc, the benzyl substituent 6a showed similar activity as that
weak inhibitory activity (1.66 μM). Indeed, phenyl substituent
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Table 4. In Vitro 11β-HSD1 Inhibitory Activity, Liver Microsomal Stability, and 11β-HSD 1 Inhibition of Cyclic Sulfonamide
Derivatives
a
b
c
(E)-Adamantylcarboxamide isomer. IC50 values were determined by GraphPad Prism software. The chirality of methyl is racemic. Results of
in vivo 11β-HSD1inhibition are expressed as means SEMs for n = 4 mice per group. **P < 0.01, ***P < 0.001 vs vehicle group.
Table 5. Selectivity, Stability, CYP Inhibition, hERG, Solubility, and Acute Toxicity of 18e
entry
hHSD2 inhibition
plasma stability
CYP inhibition
hERG
aqueous solubility
acute toxicity
18e
20% at 10 μM
100% after 30 min incubation
1A2 > 100 μM
2C9 > 100 μM
2C19 > 100 μM
2D6 > 100 μM
3A4 > 100 μM
36.9 μM
361 μM
LD50 > 1000 mpk
a
Table 6. In Vivo PK and PD Study of 18e
rat PK (10 mpk)
in vivo 11β-HSD1 inhibition (po) in mice (ex vivo) monkey PK (10 mpk) in vivo 11β-HSD1 inhibition (po) in monkey (ex vivo)
po Cmax = 3.1 μg/mL
t1/2 = 3.8 h
(1 mpk) fat (76.6 2.8%)
(5 mpk) fat (90.4 0.6%)*
(10 mpk) fat (90.7 2.6%)*
(20 mpk) fat (95.9 0.8%)***
po Cmax = 6.4 ug/mL
t1/2 = 3.4 h
10 mpk
shoulder fat 87%
Inguinal fat 83%
abdominal cavity fat 81%
AUC = 15.7 μg h/mL
Cl (L/h/kg) = 0.7
F = 68.8%
AUC = 35.6 μg h/mL
a
Results of in vivo 11β-HSD1 inhibition in rats (?) are expressed as means SEMs for n = 4 mice per group. In in vivo 11β-HSD1 inhibition in
monkeys, results are expressed as means for n = 2 monkey per group *P < 0.05, and ***P < 0.001 vs vehicle group.
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13a showed good in vitro activity with an IC50 value of 12 nM.
However, 1-adamantyl derivative 13b and acid compound 12
were weakly active and not active, respectively.
and mouse 11β-HSD1, selectivity toward 11β-HSD2, metabolic
stability, good PK and safety profiles such as hERG, CYP, and
acute toxicity. Additionally, 18e also showed good in vivo
efficacy in a primate model.
We focused our attention on N-phenylsubstituted cyclic
sulfamide with adamantylcarboxamide (13c), which has better
microsomal stability than unsubstituted adamantyl group,16 and
the results are summarized in Table 2. Compounds 13c−h
are E isomers, which showed better in vitro activity than the
Z isomers; therefore, we focused on the E isomer. Unsubstituted
phenyl derivative with adamantylcarboxamide (13c) showed
good in vitro activity with an IC50 value of 17 nM for human
11β-HSD1 and moderate activity with an IC50 value of 207 nM
for mouse 11β-HSD1. Although 3-fluoro (13e), 4-fluoro (13f),
and 2,4,6-trifluorophenyl (13g) derivatives showed moderate to
good in vitro activities, 2,4,6-trichlorophenyl derivative (13h)
was the most active in this series with 1 and 4 nM for human
and mouse 11β-HSD1, respectively.
ASSOCIATED CONTENT
* Supporting Information
■
S
Synthetic procedures and details of biological assay. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jhahn@krict.re.kr.
■
Author Contributions
§These authors contributed equally.
The compound 13h showed good in vitro activities;
therefore, we performed in vivo 11β-HSD1 inhibition study
in normal mice. After 20 mpk oral dosing, 11β-HSD1 inhibition
was measured in fat and liver tissues. Compound 13h showed
86 and 85% 11β-HSD1 inhibitions in the fat and liver tissues
after 2 h, respectively. However, human and rat liver micro-
somal stabilities of 13h were moderate with 61 and 57% of the
parent compound remaining after 30 min of incubation. To
improve the liver microsomal stability, we changed the six-
membered ring to five- or seven-membered ring and ring-
opening structure. Unfortunately, the five-memered ring (18a)
exhibited reduced activity with submicromolar potency. More-
over, although the seven-membered ring (18b) and ring-opened
dimethyl derivative (18c) showed good in vitro potencies, their
in vivo 11β-HSD1 inhibitions and liver microsomal stabilities
were not improved.
Therefore, we further modified the six-membered ring with
diverse substituents, and the results are summarized in Table 4.
2-Methyl substituent (18d) showed improved metabolic
stability in human and rat liver microsome. Furthermore, 18e
was the most potent in this series exhibiting good in vitro
activities with 1 and 2 nM toward human and mouse 11β-
HSD1, respectively, as well as liver microsomal stability (93 and
78% after 30 min of incubation). Compound 18e exhibited the
best in vivo 11β-HSD1 inhibition efficacy with 95% inhibition
after 20 mpk oral administration.
As shown in Table 5, 18e exhibited good selectivity against
11β-HSD2 and plasma stability. Additionally, 18e showed no
significant inhibition any of the major CYP isoforms (main
cytochrome P450 enzymes, 1A2, 2C9, 2C19, 2D6, and 3A4).
Moreover, it showed weak inhibition of the hERG channel
(36.9 μM), reasonable solubility (361 μM), and a LD50 value of
over 1000 mpk.
The PK and PD profiles of 18e were evaluated in rat and
monkey and are summarized in Table 6. Compound 18e
showed good bioavailability (69%) and moderate clearance
(CL = 0.7) in rat. The compound 18e significantly and dose
dependently reduced 11β-HSD1 activity in fat tissues in 2 h by
77, 90, 91, and 96% at 1, 5, 10, and 20 mpk, respectively.
Additionally, a nonhuman primate (cynomologous monkey)
was dosed orally with 18e at 10 mpk and exhibited over 80%
11β-HSD1 inhibition in three fat depots in 2 h and a good
blood exposure level.
Funding
This research was supported by the Center for Biological
Modulators of the 21st Century Frontier R&D Program,
Ministry of Education, Science and Technology, and by the
Ministry of Knowledge Economy (Grant nos. 2011-10033279
and TS113-02).
Notes
The authors declare no competing financial interest.
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