1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazines, a novel class of 11?-HSD1 inhibitors for the treatment of diabetes

Article abstract of DOI:10.1016/j.bmcl.2013.05.102

Racemic cis-1,1-dioxo-5,6-dihydro-[4,1,2]oxathiazine derivative 4a was isolated as an impurity in a sample of a hit from a HTS campaign on 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). After separation by chiral chromatography the 4a-S, 8a-R enantio

Full text of DOI:10.1016/j.bmcl.2013.05.102

Bioorganic & Medicinal Chemistry Letters 23 (2013) 4685–4691
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Bioorganic & Medicinal Chemistry Letters
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1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazines, a novel class of 11ß-HSD1
inhibitors for the treatment of diabetes
Thomas Böhme a, Christian K. Engel a, Géraldine Farjot b, Stefan Güssregen a, Torsten Haack a,
Georg Tschank a, Kurt Ritter a,
⇑
a Sanofi Deutschland GmbH, R&D, Industriepark Höchst, 65926 Frankfurt am Main, Germany
b Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Racemic cis-1,1-dioxo-5,6-dihydro-[4,1,2]oxathiazine derivative 4a was isolated as an impurity in a sam-
ple of a hit from a HTS campaign on 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1). After sepa-
ration by chiral chromatography the 4a-S, 8a-R enantiomer of compound 4a was identified as the true,
potent enzyme inhibitor. The cocrystal structure of 4a with human and murine 11ß-HSD1 revealed the
unique binding mode of the oxathiazine series. SAR elucidation and optimization in regard to metabolic
stability led to monocyclic tetramethyloxathiazines as exemplified by compound 21g.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 18 April 2013
Revised 29 May 2013
Accepted 31 May 2013
Available online 11 June 2013
Keywords:
11b-Hydroxysteroid dehydrogenase type 1
11b-HSD1 inhibitors
Diabetes
1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazine
The enzyme 11b-hydroxysteroid dehydrogenase type 1 (11b-
HSD1) is highly expressed in human liver and adipose tissue and
uses NADPH as cofactor for the intracellular conversion of corti-
sone to the biologically active cortisol.1 Cortisol is a key regulator
of metabolic processes by modulating tissue-specific gene expres-
sion through activation of the glucocorticoid receptor. In the liver,
cortisol induces the expression of genes responsible for gluconeo-
genesis and glycogenolysis resulting in an increased hepatic glu-
cose output. Promotion of preadipocyte differentiation to mature
adipocytes by cortisol causes hyperplasia of the adipose tissue.2
Thus, selective inhibition of this enzyme offers the potential as a
novel treatment for type 2 diabetes and hyperlipidemia by control-
ling the local tissue-specific cortisone/cortisol levels.
The sp2-nitrogen of inhibitors with heteroaromatic groups such
as pyridine5c,d or triazole5e can also take on this role. Depending on
their substitution pattern, 2-aminothiazolones5f,g exhibit alterna-
tive binding modes in the active site due to tautomerism.
Several compounds (BMS-770767,6a HSD-016,6b BI-135585,4j
BMS-816336, LY2523199, RG-4929) have been reported to have
been evaluated in Phase I and II clinical trials for their ability to re-
duce glucose levels and HbA1c in diabetic patients. The published
structures of the clinical candidates are shown below
OH
N
Cl
N
F3C
CF3
O
S
O
N
OH
N
N
F
O
Many pharmaceutical companies are engaged in the search for
orally available 11b-HSD1 inhibitors for the treatment of type 2
diabetes.3a–f Most of the published structures of 11b-HSD1 inhibi-
tor classes feature a moiety with an H-bond acceptor functionality
(acids,4a amides,4b–f lactams,4g,h ureas4i and carbamates4j) flanked
by bulky lipophilic residues such as adamantyl or bicyclooctanyl
residues. The carbonyl function in these compounds occupies the
position of the reducible ketofunction of the substrate cortisone
and is involved in a similar hydrogen bonding network in the ac-
tive site as shown by several X-ray structures with the human
11b-HSD1.3f,4c–f,5a,b,7a,b
HSD-016
BMS-770767
O
HO
F
O
N
F
BI-135585
F
In our endeavour to find new oral treatments for type 2 diabetes,
we recently reported the identification of a new class of potent
and selective inhibitors of 11b-HSD1 (pyrrolidine-pyrazole ureas
⇑
Corresponding author. Tel.: +49 69 305 29027; fax: +49 69 305 942805.
E-mail address: kurt.ritter@sanofi.com (K. Ritter).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.05.102

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T. Böhme et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4685–4691
Cl
S
1) and their subsequent optimization in regard to ADME profile
and ex vivo activity in target tissues.7a,b
Cl
a
c
H
N
H
N
A second series was found from the high-throughput screening
campaign on 11b-HSD1. This series originated from former syn-
thetic efforts in the area of KATP-blocking sulfonylureas, which
are now well-established antidiabetic drugs.8 The sulfonylureas
of the general structure 2 had only weak blocking activities of
SO2NCO
O
O
6
7 rac.
O
b
9 rac.
d
the KATP channel (IC50 >1 lM).
SO2NCO
c
8
R
N
H
N
H
N
N
H
H
H
N
Ar
H
N
H
N
N
N
O
R
S
e
NH
S
O
O
O
O
N
S
O
O
O
1
2
O
O
3
cis-4a rac.
During evaluation of this hit series, the sulfonylurea 3 was more
active (IC50 = 117 nM) than the corresponding cyclohexyl or phenyl
compound in the screening assay with human 11ß-HSD1. The
activity was measured from a DMSO stock solution from the com-
pound library. Purity check of the original, solid batch showed that
the sample had only a purity of 65%. After purification by column
chromatography the pure compound 3 inhibited human 11b-
Scheme 1. Synthesis of racemic oxathiazine cis-4a. Reagents and conditions: (a)
ClSO2NCO, AIBN, CCl4, 85 °C, 6 h, 70–90% (crude); (b) tributylamine, benzene, 40 °C;
(c) cyclohexylamine, diisopropylethylamine, CH2Cl2, 0 °C, 1 h; 51%; (d) NaOH,
dioxane, 100 °C, ꢀ1 h, 10% (precipitate); (e) NaOH, dioxane, 100 °C, ꢀ1 h (dissolu-
tion of precipitate).
HSD1 with an IC50 of only 2.2 lM.
H
H
H
N
OH
O
S
O
a
b-c
H
N
O
S
H
N
H
N
N
SO2NH2
SO2NH2
S
N
O
O
O
O
O
O
O
10
11
trans-5a rac.
cis-4a
trans-5a
3
Scheme 2. Synthesis of racemic oxathiazine trans-5a. Reagents and conditions: (a)
BH3 Me2S, THF, quant; (b) KOtBu, NMP, rt; then cyclohexylisothiocyanate, 10 min;
(c) NBS, rt, 2 h, separation of cis- and trans-diastereomers, 50% (from 11).
We started a hunt for the ‘highly active impurity’ which often has
been a frustrating activity in drug discovery. However, in this case
the original batch was found to contain a sufficient amount of a de-
fined, stable compound. It had the same molecular weight as the
sulfonylurea 3 and was separable from 3 by column chromatogra-
phy. To our delight, the isolated compound had an IC50 of 31 nM
against human 11b-HSD1, which explained the screening result
with the original impure batch of 3. NMR-studies indicated that
the molecule contained no double bond, but had the bicyclic struc-
ture 4a with an oxathiazine scaffold and a cis-ring conjunction. For
an unequivocal proof of structure we prepared the cis- and trans-
isomers 4a and 5a in racemic form by independent routes.
Chlorosulfonylisocyanate, discovered at Hoechst AG in Frankfurt
in the mid fifties, has a fascinating chemistry.9 It adds to olefins to
give b-lactams after hydrolysis. However, in the presence of radical
initiators such as AIBN, the reaction with olefins, for example cyclo-
hexene, yields 2-chloroalkylsulfonylisocyanates such as 7. Vinyl-
sulfonylisocyanate 8, obtained by elimination of HCl with a
tertiary amine, reacts with primary amines to yield the correspond-
ing sulfonylureas such as 310 (Scheme 1). On the other hand, we
were able to add first cyclohexylamine to the sulfonylisocyanate
7 and then realized an intramolecular cyclisation under basic con-
ditions to racemic 4a. However, only a low yield was obtained
due to the characteristics of consecutive reactions (9 to 4a to 3).
High temperature was necessary to initiate the cyclisation of 9 to
4a. The progress of the reaction could be followed by the formation
of a precipitate of compound 4a. But then subsequent elimination
to the more soluble 3 occured. Longer reaction times led to the com-
plete degradation of the desired product 4a to the compound 3. The
route explains also the observation that the cis-isomer 4a was ob-
tained as single isomer due to a trans-addition in the radical step
and a SN2-mechanism in the cyclisation step. On the other hand,
we were not able to convert 3 back to 4a under various conditions.
For the synthesis of the trans-isomer, racemic 2-oxo-cyclohexyl-
sulfonamide11 10 was reduced to a mixture of diastereomers 11
(trans/cis-ratio: 63/37). Addition of cyclohexylisothiocyanate and
subsequent cyclisation by N-bromosuccinimide gave the pure,
racemic trans-isomer 5a after purification (Scheme 2).
Next, we separated the two diastereomeric pairs by chiral chro-
matography, one cis-diastereomer was much more active than the
other diastereomers (Table 1).
We determined the absolute configuration (4a-S, 8a-R) of the
most active cis-enantiomer 4a by X-ray crystallography.
S
H
O
N
N
S
H
R
O O
4a
For crystallization studies with the human and mouse 11ß-HSD1
enzyme we used the racemic mixture of 4a. The structures were
solved at a resolution of 1.96 Å (R-factor 16.8%, R-free 20.3%) for
the human enzyme and 2.21 Å (R-factor 16.7%, R-free 21.0%) for
Table 1
Activity of pure diastereomers
Diastereomer
IC50 (lM)
Human
Mouse
0.328
Rat
A/cis-4a
B/cis-4a
C/trans-5a
D/trans-5a
0.024
0.575
0.197
0.655
0.246
0.572
1.140

T. Böhme et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4685–4691
4687
Ala172
NH
Tyr183
HO
O
O
H
S
N
H
O
N
H
Figure 1. Active site of human (1a) and murine (1b) 11ß-HSD1 in complex with ligand 4a.
site residue, Ser170, is not directly interacting with the inhibitor.
One of the sulfonyl oxygen atoms forms an anchoring hydrogen
bond to the main chain nitrogen of Ala172, the second sulfonyl
oxygen forms a water-mediated hydrogen bond to the protein.
The cyclohexylamine ring is in chair conformation and points into
a buried, water-filled pocket formed by the cofactor NADPH and
the protein stretches Ile121-Thr126 and Thr222-Val227. The fairly
small cyclohexyl moiety does not completely fill the buried pocket,
indicating the possibility to include bulkier or bridged ring systems
in this position. The bicyclic oxathiazine ring is oriented towards a
solvent access channel to the binding pocket, offering a possibility
to extend the compound into this water-filled channel. Only the
4a-S, 8a-R enantiomer of compound 4a can bind in this particular
binding mode to 11b-HSD1. Without adjustment of the binding
mode or surrounding protein residues the second cis-enantiomer
and the trans-isomers clash with the protein. The annellated cyclo-
hexyl moiety points towards residue 177. This residue is one of the
main differences between human and murine 11b-HSD1, featuring
a tyrosine side chain in the human enzyme and a glutamine in the
murine enzyme. For Tyr177 of human 11b-HSD1 we observe elec-
tron density for two alternate tyrosine side chain conformations
within the same crystal structure, indicating a certain flexibility
of the human enzyme in this region. The side chain is in a typical
van-der-Waals distance to the inhibitor. In contrast, Gln177 in
Table 2
SAR around racemic 4 and 5
R
R
H
N
O
X
N
SO2
Compd
X
R
Human IC50 (lM)
cis-4a
cis-4b
cis-4c
trans-5c
cis-4d
trans-5d
cis-4e
CH2
CF2
O
H
H
H
H
H
H
H
Me
0.031
0.234
1.220
0.799
>2.250
>2.250
>2.250
0.018
O
NH
NH
NMe
CH2
cis-16
the murine enzyme. The compound is unambiguously defined in
both cases. In the crystal structure we found exclusively the 4a-S,
8a-R enantiomer of compound 4a bound to the steroid binding site
of 11b-HSD1 (Fig. 1a and b). Compound 4a binds in an identical
fashion to the steroid binding site of the human and the murine en-
zyme. The cyclohexyl-NH interacts with the key active site residue
Tyr183 involved in substrate ketone reduction. The second active
H
H
H
N
H
H
H
N
O
S
O
S
g
X
N
N
N
d-e ( X= CF2 and O )
O
d-f ( X= NBoc to
O
O
O
O
cis-4b-d
cis-4e
O
N
O
X= NH)
OH
rac
b
rac
c
a
X
+
X
X
X
SO2NH2
SO2NH2
H
12
H
N
14
13
15
O
X = CF2
X = O
X = NBoc
X
N
S
O O
H
trans-5c-d
rac
Scheme 3. Synthesis of oxathiazines 4b–e and 5c–d. Reagents and conditions: (a) morpholine, toluene, reflux, 5 h, 91–100%; (b) ClSO2NH2, diisopropylethylamine, THF,
À40 °C to rt, 16–81%; (c) NaBH4, MeOH, 42–64%; (d) KOtBu, DMF or NMP, rt, 5 min; then cyclohexylisothiocyanate, 5 min; (e) NBS, rt, 5 min; separation of diastereomers, 12–
36% (from 15); (f) TFA, CH2Cl2, rt, 15 min, quant.; (g) paraformaldehyde, Na(CN)BH3, AcOH, THF, rt, 16 h, 59%.

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T. Böhme et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4685–4691
the murine 11b-HSD1 is found in a clearly defined single confor-
mation. This conformation places the glutamine side chain consid-
erably closer to the inhibitor. The suboptimal distance between
ligand and protein at this position is contributing to the 40-fold
lower in vitro activity on the murine enyzme.
A concern with the oxathiazine core structure was the chemical
stability as well as the stability in plasma. However, under acidic
and neutral conditions compound 4a was stable. Studies in plasma
with compound 4a also showed no significant degradation of com-
pound 4a.
To assess the ability of our compounds for inhibition of 11b-
HSD1 in target tissues, especially liver and adipose tissue, we
established a pharmacodynamic assay.7a,7b Our goal was to in-
crease human and rodent activity and obtain sufficient metabolic
stability for in vivo studies.
Firstly, we carried out some modifications in the annellated
cyclohexyl ring of the oxathiazine core structure (Table 2).
Introduction of heteroatoms (O, N) or a CF2 group in position 7 of
the oxathiazine core (X = CF2, O, N, NMe; compounds 4b–e and
5b–d), using the chemistry developed for the trans-isomer
(Scheme 3), led to considerable loss of activity. However, replacing
the hydrogens at the bridging carbons by methyl groups (com-
pound 16, synthesis in Scheme 4) is possible with slight improve-
ment of the activity on the human 11b-HSD1.
For rapid SAR evaluation in regard to the cycloalkylamine part,
the racemic cis-derivatives 4f–w were obtained by the same route
as described in Scheme 1 despite moderate yields (Table 3).
Increasing the ring size from five to eight led to an improvement
of activity against the human and rodent 11b-HSD1, but also to
an increase in metabolic lability. Thus, we prepared compounds
with monocyclic (4-dimethylcyclohexyl, 3,3,5,5-tetramethyl-
cyclohexyl), bicyclic (bicyclo[3.3.0]- or bicyclo[2.2.2]octanyl) and
tricyclic (adamantyl, noradamantyl) ring systems, but the most po-
tent and lipophilic ones such as 4l, 4q, 4t or 4w showed high met-
abolic lability.
Attempts to block potential metabolic hot spots by a hydroxyl
group at these positions improved metabolic stability, but led to
considerable loss of activity against human and rodent enzymes,
for example in the case of the bicyclo[2.2.2]octanyl derivative 4s.
Aniline could not replace the cyclohexylamine moiety (com-
pound 4m), however, the corresponding benzylamine derivative
4o or cyclohexylmethylamine derivative 4n showed only a three
to fourfold drop in activity compared to 4a.
In order to improve metabolic stability, we introduced polar
side chains at the alpha-position of the benzyl amine (Table 4).
Two methyl groups (4x) at the benzylic position diminished the
activity against 11b-HSD1, however oxathiazines with chiral ami-
no alcohols showed an increase in activity. A clear SAR was seen
for the carbon chain length 1 < 2 > 3 (17b, d, and e) as well as for
the chirality at the benzylic center (17a–d). Compounds with other
polar moieties such as an amino (17f) or amide residues (17g–h)
were less active. However, metabolic stability was still not satisfac-
tory for the most active 17d. Metabolite studies with this com-
pound showed that only one metabolite is formed by oxidation
of the annellated cyclohexyl ring (data not shown).
Compound cis-16 (Table 2) with two additional methyl groups
at the ring conjunction was quite potent. We wondered if we could
remove the annellated cyclohexyl ring. Thus, we synthesized
monocyclic tetramethyloxathiazines 21a–h (Scheme 4) reducing
the number of stereogenic centers. We used the rich chemistry of
chlorosulfonylisocyanate and its derivatives such as 18a–b. Treat-
ment of N-chlorosulfonylcarbamates 18a–b with sodium hydride
in the presence of olefins13 such as 1,2-dimethylcyclohexene or
2,3-dimethylbutene gave the corresponding 1,4-cycloadducts 19
or 20a–b, albeit in low yields. Reaction of these cycloadducts with
the appropriate amines led to 16 and 21a–g. Treatment of the
similarly obtained ester 22 with excess Grignard reagent gave
the alcohol 21h.
We also prepared spiro-oxathiazines 26a–d as depicted in
Scheme 5. Deprotonation of the Boc-protected cyclopropylsulfona-
mide 23,14 addition of the appropriate ketone or aldehyde and sub-
sequent removal of the Boc-protecting group gave the ß-hydroxy
sulfonamides 24a–d. Addition of cyclohexylisothiocyanate and
cyclisation with N-bromo-succinimide led to the spiro-oxathia-
zines 26a–d.
The tetramethyloxathiazine 21a was more potent than the
spiro-oxathiazines 26 against human 11b-HSD1 enyzme (Table 5).
The SAR for the corresponding N-benzyl-derivatives 21b–h is
shown in Table 6. Potency against human 11b-HSD1 is in the
range of 4–15 nM, whereas the compounds were less active
against the murine enzyme (26–452 nM). Compound 21e with a
chloro-substituent in 2-position showed high activity against
Table 3
SAR of racemic cis-oxathiazines 4f–w; variation of ring
H
H
N
O
R
N
rac
SO2
H
Compd
R
IC50 (
Human
l
M)
Metabolic lability12 (%)
Mouse
Human
Mouse
4f
0.425
0.031
4a
1.220
0.087
18
45
19
54
4g
4h
0.022
0.013
0.031
79
84
4i
0.671
0.406
0.064
O
F
F
4j
4k
0.455
0.057
55
93
55
97
4l
0.011
4m
4n
0.675
0.080
0.729
0.786
4oa
4p
0.104
0.008
0.047
4qa
4r
0.016
0.024
0.065
0.275
0.454
0.695
94
87
F
4s
OH
12
91
20
98
4ta
0.004
0.063
0.040
0.400
4u
OH
4v
0.027
0.004
0.076
0.009
4w
83
65
a
More active enantiomer.

T. Böhme et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4685–4691
4689
Table 4
SAR of N-benzyl-oxathiazines (diastereomeric mixtures of cis-oxathiazines)
H
N
O
R1
R2
N
SO2
Compd
R1
R2
IC50
(l
M)
Metabolic lability12 (%)
Human Mouse
Human
Mouse
4o
4x
H
Me
–CH2OH
H
H
Me
H
CH2OH
H
–(CH2)2OH
–(CH2)3OH
–(CH2)2NH2
–CH2CONH2
–CH2CONHMe
0.104
0.215
>2.250
0.050
1.480
0.011
0.038
1.580
0.334
0.652
0.786
0.444
17a
17b
17c
17d
17e
17f
17g
17h
0.152
–(CH2)2OH
H
H
H
H
H
0.016
0.294
77
89
41
78
47
35
human and murine enzymes, but lacked metabolic stability in
murine microsomes. Compound 21g with a 4-fluoro-substituent
showed good metabolic stability and high potency against human
11b-HSD1, but was considerably less active against the murine
enzyme.
In conclusion, the starting point for a new class of 11b-HSD1
inhibitors was found as an impurity in a hit sample from a HTS
campaign on this enzyme. 1,1-Dioxo-5,6-dihydro-[4,1,2]oxa-thia-
zine derivative 4a was isolated as racemate from the original
sample and its structure proven by an independent synthesis. After
separation by chiral chromatography the (4a-S, 8a-R)-enantiomer
of 4a was identified as the true, potent enzyme inhibitor of 11b-
HSD1. Co-crystal structures with human and murine enzyme re-
vealed the unique binding mode of the oxathiazine series. Potency
could be improved by introduction of bulky bi- and tricycles, how-
ever the resulting compounds displayed low metabolic stability.
Modifications around the oxathiazine core structure led to potent
and metabolically stable tetramethyloxathiazines as illustrated
H
O
S
N
H
O
S
O
a
b
c
OAr
Cl
N
Cl
N
C
O
S
S
N
N
O
O
O
NO2
O
O
O
O
O
O
18a Ar = 4-NO2Ph
18b Ar = 2,6-DiF-Ph
19
16
H
N
O
d
R
N
S
e
O
O
O
S
OAr
21a-g
N
Cl
O
O
Cl
e
H
N
H
O
S
N
O
f
20a Ar = 4-NO2Ph
N
N
S
20b Ar = 2,6-DiF-Ph
CO2Me
O
O
O
O
OH
22
21h
Scheme 4. Synthesis of oxathiazines 16 and 21a–h. Reagents and conditions: (a) ArOH, CH2Cl2, rt, 1.5 h, quant (crude); (b) NaH, THF, À78 °C, then 1,2-dimethylcyclohexene,
À78 °C to 35 °C, 30 min, 10%; (c) cyclohexylamine, diisopropylethylamine, CH2Cl2, rt, 17%; (d) NaH, THF, À78 °C, then 2,3-dimethylbutene, À78 °C to 35 °C, 30 min, 16–24%;
(e) R-NH2, diisopropylethylamine, CH2Cl2, rt, 23–81%; (f) MeMgBr, THF, 18%.
4R
3R
4R
3R
4R
3R
H
d
OH
O
S
N
OH
a-c
e-f
SO2NHBoc
N
SO2NHBoc
SO2NH2
23
O
O
26a-d
24a-d
25a-d
Scheme 5. Synthesis of spiro-oxathiazines 26a–d. Reagents and conditions: (a) 2 equiv BuLi, THF, À78 °C; (b) R3-(C@O)-R4, À78 °C to rt; (c) NH4Cl, 33–39% (from 23); (d) 1 N
HCl, EtOAc, 70 °C, 10 h, 73–83%; (e) KOtBu, NMP, rt, 5 min; then cyclohexylisothiocyanate, 10 min; (f) NBS, rt, 1 h, 13–39% (from 25).

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T. Böhme et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4685–4691
Table 5
SAR of tetramethyloxathiazine 21a and spiro-oxathiazines 26a–d
4R
3R
H
N
O
2R
1R
N
SO2
Compd
R1, R2
R3, R4
IC50
(
lM)
Metabolic lability12 (%)
Mouse
Human
Mouse
Human
5
21a
26a
26b
26c
26d
Me, Me
Me, Me
Me, Me
–(CH2)3–
–CH2–O–CH2–
Et, H
0.018
0.028
0.082
0.139
0.177
0.865
1.620
0.813
9
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
2.510
Table 6
SAR of tetramethyloxathiazines 21b–h
O
N
R
X
N
SO2
Compd
R
X
IC50
(lM)
Metabolic lability12 (%)
Mouse
Human
Mouse
Human
21b
21c
21d
21e
21f
Me
Me
H
2-Cl
H
2-Cl
3-CN
4-F
2-Cl
0.015
0.004
0.007
0.004
0.006
0.007
0.010
0.286
0.029
0.232
0.026
0.110
0.199
0.452
–(CH2)2OH
–(CH2)2OH
–(CH2)2OH
–(CH2)2OH
–CH2–CMe2OH
4
25
11
52
21g
21h
2
9
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by compound 21g. Further optimization of this new class of 11b-
HSD1 inhibitors will be the subject of upcoming papers.
Acknowledgements
We thank Regina Brunnhöfer for construction and purification
of recombinant human and murine 11ß-HSD1 as well as Dr.
Gerhard Kretzschmar for his support in the synthesis of the
trans-oxathiazine and Dr. John Weston for helpful discussions.
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