Discovery of 2-alkyl-1-arylsulfonylprolinamides as 11β-hydroxysteroid dehydrogenase type 1 inhibitors

Article abstract of DOI:10.1021/ml300144n

On the basis of scaffold hopping, a novel series of 2-alkyl-1- arylsulfonylprolinamides was discovered as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) inhibitors. A representative compound 4ek, obtained through SAR and structure optimization studies, demonstrates excellent in vitro potency against 11β-HSD-1 and dose-dependent in vivo inhibition of 11β-HSD-1 in a prednisone/prednisolone transformation biomarker study in mice.

Full text of DOI:10.1021/ml300144n

Letter
pubs.acs.org/acsmedchemlett
Discovery of 2‑Alkyl-1-arylsulfonylprolinamides as 11β-
Hydroxysteroid Dehydrogenase Type 1 Inhibitors
Jianxin Yu,†,§ Haiyan Liu,†,§ Guangxin Xia,*,†,‡ Lin Liu,†,‡ Zhenmin Xu,† Qian Chen,† Chen Ma,†
Xing Sun,† Jiajun Xu,† Hua Li,† Ping Li,† Yufang Shi,† Bing Xiong,‡ Xuejun Liu,† and Jingkang Shen*,†,‡
†Central Research Institute, Shanghai Pharmaceutical Holding Co., Ltd., Building 5, 898 Ha Lei Road, Zhangjiang Hi-Tech Park,
Shanghai 201203, China
‡State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Zhangjiang Hi-Tech Park, Shanghai 201203, China
S
* Supporting Information
ABSTRACT: On the basis of scaffold hopping, a novel series of
2-alkyl-1-arylsulfonylprolinamides was discovered as 11β-hydrox-
ysteroid dehydrogenase type 1 (11β-HSD-1) inhibitors. A
representative compound 4ek, obtained through SAR and
structure optimization studies, demonstrates excellent in vitro
potency against 11β-HSD-1 and dose-dependent in vivo
inhibition of 11β-HSD-1 in a prednisone/prednisolone trans-
formation biomarker study in mice.
KEYWORDS: metabolic syndrome, enzyme inhibitor, 11β-hydroxysteroid dehydrogenase type 1, sulfonamide, 2-alkylproline,
prolinamide
lucocorticoid receptor (GR) signaling plays a significant
Grole in metabolic regulation, and defects in this signaling
pathway have been implicated in the development of several
phenotypes of metabolic syndrome.1 GR signaling depends not
only on the circulating cortisol levels but also on the
intracellular production of cortisol through reduction of
cortisone, the inactive glucocorticoid. The enzymes catalyzing
the conversion between cortisone and cortisol are 11β-
hydroxysteroid dehydrogenases (11β-HSDs). Among them,
the type 1 isoform (11β-HSD-1), highly expressed in liver and
adipose tissue, predominantly reduces cortisone to cortisol, and
the type 2 isoform (11β-HSD-2), primarily expressed in kidney,
oxidizes cortisol to cortisone. A potential role for 11β-HSD-1
inhibitors in metabolic syndrome, type 2 diabetes, and obesity
has been established using transgenic mice.2−4 On the basis of
Figure 1. 11β-HSD-1 inhibitors. Combining the arylsulfonyl moiety of
these findings, in recent years, 11β-HSD-1 is recognized as a
1a or 1b with the D-prolinamide moiety of PF-877423 (2) to discover
2-alkyl-1-arylsulfonylprolinamide 4a.
promising target in metabolic disease.1−4
In the past decade, industrial and academic researchers have
reported several classes of 11β-HSD-1 inhibitors with varied
scaffolds, including sulfonamides (e.g., BVT-14225, 1a), amides
I/II trials for potential oral treatment of metabolic
diseases.10−12
(e.g., PF-877423, 2) (Figure 1), triazoles (e.g., Merck 544), and
thiazolones (e.g., AMG-221).5−8 In a phase II clinical trial, 11β-
HSD-1 inhibitor INCB-13739 (structure undisclosed) signifi-
cantly improved insulin sensitivity in type 2 diabetes patients
who failed on metformin treatment and lowered triglyceride
and cholesterol levels of patients with hyperlipidaemia and
hypertriglyceridemia.9 Currently, other examples such as PF-
915275, MK-0916, and AZD-4071 are being evaluated in phase
We recently disclosed a new series of sulfonamides (e.g., 1b,
Figure 1) with high inhibitory activity against 11β-HSD-1, and
compound 1b showed a short duration of action in a
pharmacodynamics (PD) model.13 As part of our continuing
Received: June 11, 2012
Accepted: September 18, 2012
© XXXX American Chemical Society
A
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ACS Medicinal Chemistry Letters
Letter
a
Scheme 1. Synthesis of Compounds 4a−g and 8a,b,e
Table 2. In Vitro Potency of (S)-Enantiomers
a
Reagents and conditions: (a) CH3OH, SOCl2, reflux, 1 h. (b) 3-
Chloro-2-methylbenzene-1-sulfonyl chloride, triethylamine, CH2Cl2,
rt, 2 h. (c) NaOH, THF, CH3OH, H2O, rt, overnight. (d) RNH2,
BOP-Cl, DIPEA, CH2Cl2, rt, 6 h.
Table 1. In Vitro Potency of (R)-2-Methyl Prolinamides with
Varied Amino Groups
a
Average of at least two replicates; ND, not determined.
a
Scheme 2. Synthesis of Compounds 4eb−el
a
Reagents and conditions: (a) (Boc)2O, Na2CO3, dioxane, H2O, rt,
0.5−2 h. (b) trans-4-Aminoadamantan-1-ol hydrochloride, BOP-Cl,
DIPEA, CH2Cl2, rt, overnight. (c) CF3COOH, CH2Cl2, rt, 1−6 h. (d)
ArSO2Cl, DIPEA, CH2Cl2, rt, 2−16 h.
μL/min/mg). In vitro metabolite identification studies
indicated that the pyrrolidine ring of compound 3 was oxidized
by HLM. We thought the substituent (e.g., alkyl) on the ring
might be helpful to slow down the oxidization, so we first
selected the commercially available (R)-α-methyl proline as a
starting material and obtained compound 4a. Interestingly, 4a
exhibited not only better HLM stability but also dramatically
increased potency (IC50 = 77 nM). Utilizing 4a as a starting
point, we discovered and elaborated a series of 2-alkyl-1-
arylsulfonylprolinamides as potent and selective 11β-HSD-1
inhibitors. Herein, we report the synthesis, structure−activity
relationship (SAR), and optimization of this series.
2-Alkyl-1-arylsulfonylprolinamide derivatives have been
prepared according to Schemes 1−3. The inhibitory activity
of this series of compounds against h-11β-HSD-1 and mouse
11β-HSD-1 (m-11β-HSD-1) was determined by scintillation
proximity assay (SPA) method,13−15 and the results are listed in
Tables 1−5. The selectivity over human 11β-HSD-2 (h-11β-
HSD-2) and 3T3L1 cellular activity of some representative
compounds was also tested.
As seen in Scheme 1, esterification of (R)-2-methylpyrroli-
dine-2-carboxylic acid (5) gave (R)-methyl 2-methylpyrroli-
dine-2-carboxylate (6). Typical sulfonylation of 6 and
saponification of the resulting ester produced carboxylic acid
a
b
Average of at least two replicates. Percent inhibition at 100 nM, the
mean of at least two experiments.
efforts to find novel and proprietary 11β-HSD-1 inhibitors, we
combined the arylsulfonyl moiety of 1a or 1b with D-
prolinamide moiety of 2 to form a new sulfonamide-D-
prolinamide represented by 3 (Figure 1), which displayed
only micromolar activity against human 11β-HSD-1 (h-11β-
HSD-1) but poor liver microsome stability (HLM Clint 430
B
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ACS Medicinal Chemistry Letters
Letter
Table 3. In Vitro Potency and Liver Microsomal Stability of (R)-2-Methyl Prolinamides with Varied Arylsulfonyl Groups
a
b
Average of at least two replicates. Percent inhibition at 100 nM, the mean of at least two experiments; ND, not determined.
7, followed by coupling with varied primary amines using bis(2-
oxo-3-oxazolidinyl)phosphonic chloride (BOP-Cl) to yield
target molecules 4a−g. As summarized in Table 1, when a
hydroxyl group is introduced to the 4-position of the cyclohexyl
moiety, the potency toward h-11β-HSD-1 increased 12-fold
(4b vs 4a); however, the methoxyl derivative 4c exhibited
reduced activity (37% at a concentration of 100 nM), and all
three compounds appeared to have very weak inhibition toward
m-11β-HSD-1 (no more than 15% at a concentration of 100
nM). The adamant-2-yl-substituted 4d and 4e showed single-
digit nanomolar and subnanomolar inhibition against human
enzyme (IC50 = 1.5 and 0.1 nM); moreover, they were also
potent inhibitors of rodent enzyme with IC50 values of 64 and
1.3 nM, respectively. However, other bridged hydrocarbon
substituents such as adamant-1-yl (4f) and 3-oxabicyclo[3.3.1]-
nonane (4g) led to poor activity versus rodent enzyme.
For comparison, using (S)-acid 9 instead of (R)-acid 5, we
synthesized (S)-form derivatives 8a, 8b, and 8e (Scheme 1). As
shown in Table 2, although the (S)-derivatives had lower
activity than the corresponding (R)-derivatives 4a, 4b, and 4e,
the adamant-2-amino analogue 8e exhibited high activity
toward both human and rodent 11β-HSD-1.
C
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ACS Medicinal Chemistry Letters
Letter
a
Scheme 3. Synthesis of Compounds 17a−c
Table 6. Profile of the Two Lead Compounds
4e
4ek
in vitro assay
a
h-11β-HSD-1 IC50
m-11β-HSD-1 IC50
0.1 nM
1.3 nM
2.2 μM
22000
7.7 nM
11 nM
>10 μM
>1300
a
a
h-HSD-2 IC50
selectivity ratio: h-HSD-2/h-11β-HSD-1 IC50
a
m-11β-HSD-1 3T3L1 cellular IC50
121 nM
11 nM
b
mice PK
CL [mL/(min kg)]
Vdss (L/kg)
iv t1/2 (min)
po F (%)
90
60
0.51
14
0.63
14
9.1%
63%
597.0
3.0%
33%
939.0
ip F (%)
ip AUC0-t (ng h/mL)
a
Reagents and conditions: (a) Triethylamine, CH2Cl2, rt, 2 h. (b)
TMS-CF3, TBAF, THF, overnight. (c) NaOH, CH3OH, THF, H2O,
rt, overnight. (d) 4-Aminoadamantane, BOP-Cl, DIPEA, CH2Cl2, 6 h.
a
b
Average of at least two replicates. Dosed iv (1 mg/kg), po (5 mg/
kg), and ip (5 mg/kg) in male BALB/c mice; mean values over three
mice.
Table 4. In Vitro Potency of Compounds 17a−c
a
h-11β-HSD-1 IC50
m-11β-HSD-1 inh. at 100
b
compd
R1
OH
(nM)
nM (%)
17a
17b
17c
6.0
43
26
9.5
14
CN
COOMe
124
a
b
Average of at least two replicates. The mean of at least two
experiments.
Table 5. In Vitro Potency of Compounds 18a,b
Figure 2. In vivo inhibitory activity of 11β-HSD-1 in BALB/c mice by
4ek. Student's t test was used to compare the differences between the
dosing group and the vehicle. *P < 0.05 vs vehicle.
have been used to prepare metabolically stable druglike
molecules.17−19 For example, introducing a hydroxyl group
on the adamantane ring reduced Clog P and blocks metabolic
soft spots.6 In our test, hydroxylated adamant-2-yl derivative 4e
possessed better stability in HLM than unsubstituted adamant-
2-yl derivative 4d (HLM Clint of 4e vs 4d: 106 vs 499 μL/min/
mg protein). Consequently, we next focused our attention on
the derivatization of 4e.
Through the route depicted in Scheme 2, we synthesized
more 4-amino-1-hydroxyl-adamantyl derivatives. (R)-1-(tert-
Butoxycarbonyl)-2-methyl pyrrolidine-2-carboxylic acid 12,
obtained from (R)-acid 5, coupled with trans-4-amino-
adamantan-1-ol hydrochloride to provide intermediate 13.
The target compounds (4eb−el) were then obtained by two
successive steps from 13: deprotection and sulfonylation. As
listed in Table 3, most of the aryl or heteroaryl groups
maintained high binding affinities to human enzyme with
single-digit nanomolar IC50 values, but some of them lose
rodent enzyme activity.
a
IC50 (nM)
compd
R2
h-11β-HSD-1
m-11β-HSD-1
4ek
18a
18b
−CH3
7.7
16
11
164
87
−CH2CH3
−CH2CHCH2
b
33%
a
b
Average of at least two replicates. Percent inhibition at 100 nM, the
mean of at least two experiments.
Because h-11β-HSD-1 enzyme shares only about 79%
homology with the mouse enzyme, it might be understandable
that many 11β-HSD-1 inhibitors displayed species-dependent
activity.5 Some clinical candidates, such as INCB-13739 and
PF-915275, lack potency against rodent enzyme, so in vivo
pharmacokinetics (PK)/PD studies of these compounds
require primate models.16 In our series, cross-species potencies
of adamant-2-yl derivatives 4d and 4e allowed us to employ
rodent model.
To extend the SAR of this series, we next explored the effect
of the R1 group on adamantane. Noticing 4-(1,1,1-trifluoro-2-
hydroxypropan-2-yl)benzenesulfonamide reported in literature
as a pharmacophore of 11β-HSD-1 inhibitors, we designed new
It is reported that the adamantane group is prone to
oxidation in living organism, which could cause a rapid
elimination of the compound, so substituted adamantanes
D
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ACS Medicinal Chemistry Letters
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derivatives 17a−c (Scheme 3 and Table 4).20 As described in
Scheme 3, sulfonylation of 6 afforded ketone 15. Intermediate
16 was generated by treatment of 15 with (trifluoromethyl)-
trimethylsilane (TMS-CF3)/tetra-n-butylammonium fluoride
(TBAF) in THF and a following hydrolysis step. The target
compounds were then produced via condensation of 16 with
the 1-substituted 4-aminoadamantanes. As listed in Table 4, the
potency against human enzyme of 17b (R1 = CN) or 17c (R1 =
COOMe) decreases 7- or 20-fold as 17a (R1 = OH). However,
all three compounds display only weak activity on rodent
enzyme at a concentration of 100 nM.
Author Contributions
§These authors contributed equally.
Funding
This work was supported by New Drug Creation Project of the
National Science and Technology Major Foundation of China
(project 2010ZX09401-404).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are indebted to Prof. Ying Leng and Yu Shen, SIMM, for
the molecular and cellular level 11β-HSDs assay.
■
To investigate the effect of R2 group on the pyrrolidine, 4ek
analogues 18a and 18b were designed (Table 5). The synthesis
of 18a and 18b is analogous to 4ek, replacing starting material
5 in Scheme 1 with (R)-2-ethyl and (S)-2-ally pyrrolidine-2-
carboxylic acid.21 As seen in Table 5, the methyl in the 2-
position of pyrrolidine is superior to ethyl and allyl groups in
terms of potency, but the 2-allyl analogue 18b has higher
affinity to rodent enzyme than human enzyme.
The potential for compounds 4e and 4ek to complete lead
candidate criteria was further evaluated (Table 6). Both
compounds were potent inhibitors of human and mouse 11β-
HSD-1 and highly selective against human 11β-HSD-2. In the
3T3L1 cell-based assay, compound 4ek was 11 times more
potent than 4e. In the mouse PK test, however, both 4e and
4ek showed high clearance, very short plasma half-life, and low
oral bioavailability.
To look at the correlation between in vitro activity and in
vivo inhibition, 4ek, with higher cellular level activity than that
of 4e, was selected as a tool compound and progressed to an in
vivo 11β-HSD-1 inhibition assay in mice. Because of the poor
metabolic stability and low oral bioavailability of 4ek, we at first
selected intraperitoneal (ip) injection as administration route
(Table 6, enhanced bioavailability after ip injection is 33%, 11
times of the po bioavailability). In this mechanistic biomarker
study, normal mice were dosed with 4ek (or vehicle) and then
exogenous substrate prednisone, which transformed to
prednisolone catalyzed by 11β-HSD1.22 As illustrated in Figure
2, ip treatment of BALB/c mice with 3, 10, and 30 mg/kg 4ek
dose- dependently reduced the generation of predinisolone
with inhibition of 34, 71, and 89%, respectively, and the
corresponding plasma concentrations of 4ek in mice were 28,
80, and 94 ng/mL.
In conclusion, we reported a new series of 2-alkyl-1-
arylsulfonylprolinamides as human and rodent 11β-HSD-1
inhibitors. Primary optimization and SAR studies led to the
discovering of compound 4ek, which demonstrated potent and
selective activity in vitro and in vivo inhibitory activity in a
prednisone conversion experiment. Efforts to improve the PK
profile of this series are under way and will be reported in the
future.
ABBREVIATIONS
■
HSD, hydroxysteroid dehydrogenase; SAR, structure−activity
relationship; HLM, human liver microsome; PK, pharmacoki-
netics; PD, pharmacodynamics; BOP-Cl, bis(2-oxo-3-
o x a z o l id i ny l) p h os p ho ni c ch lo r i de ; T M S- C F3 ,
(trifluoromethyl)trimethylsilane; TBAF, tetra-n-butylammo-
nium fluoride; DIPEA, N,N-diisopropylethylamine
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization of new chemical
entities. This material is available free of charge via the Internet
at http://pubs.acs.org.
́
(8) Veniant, M. M.; Hale, C.; Hungate, R. W.; Gahm, K.; Emery, M.
G.; Jona, J.; Joseph, S.; Adams, J.; Hague, A.; Moniz, G.; Zhang, J.;
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AUTHOR INFORMATION
■
Corresponding Author
Henriksson, M. A.; Williams, M.; Vallgarda, J.; Fotsch, C.; Wang, M.
Discovery of a potent, orally active 11.beta-hydroxysteroid dehydro-
genase type 1 inhibitor for clinical study: Identification of (S)-2-
̊
*Fax: +86 21 50128885. E-mail: xiagx@pharm-sh.com.cn
(G.X.) or jkshen@mail.shcnc.ac.cn (J.S.).
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