Piperidine amides as 11β-hydroxysteroid dehydrogenase type 1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.03.083

A series of piperidine amide inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) were identified via modifications of the HTS hit compound 1. The synthesis, in vitro biological evaluation, and structure-activity relationship of these co

Full text of DOI:10.1016/j.bmcl.2007.03.083

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3421–3425
Piperidine amides as 11b-hydroxysteroid dehydrogenase
type 1 inhibitors
a,
a
a
b
*
´
Katarina Flyren, Lars O. Bergquist, Victor M. Castro, Christopher Fotsch,
Lars Johansson,a David J. St. Jean, Jr.,b Lori Sutina and Meredith Williamsa,
aBiovitrum AB, SE-112 76 Stockholm, Sweden
bAmgen, Inc., One Amgen Center Dr, Thousand Oaks, CA 91320, USA
Received 27 February 2007; revised 27 March 2007; accepted 27 March 2007
Available online 30 March 2007
Abstract—A series of piperidine amide inhibitors of human 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) were identified
via modifications of the HTS hit compound 1. The synthesis, in vitro biological evaluation, and structure–activity relationship of
these compounds are presented.
Ó 2007 Elsevier Ltd. All rights reserved.
OH
OH
OH
11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1)
has attracted attention during the last few years due to
its potential as a target for the treatment of diseases
associated with the metabolic syndrome.1–3 The enzyme,
which is mainly expressed in liver and adipose tissue,
catalyzes the conversion of inactive cortisone to gluco-
corticoid receptor-active cortisol (Fig. 1). The type II
isoform (11b-HSD2) is located primarily in the kidney
and catalyzes the inactivation of cortisol.4
O
O
11
β
-HSD1
-HSD2
O
HO
OH
H
H
11β
H
H
H
H
O
O
cortisone
cortisol
Figure 1. Interconversion of cortisone and cortisol by 11b-HSD1 and
11b-HSD2.
A growing number of research results indicate that glu-
cocorticoid excess in tissues such as the liver and adipose
might contribute to the development of the metabolic
syndrome. In the liver, cortisol has been shown to pro-
mote gluconeogenesis via the glucocorticoid receptor
by activation of phosphoenolpyruvate carboxykinase
and glucose-6-phosphatase enzymes.5 In the adipose tis-
sue, cortisol is involved in the stimulation of adipogene-
sis, lipolysis, and release of free fatty acids.6 The
significance of 11b-HSD1 in metabolic diseases such as
type 2 diabetes and obesity has been demonstrated in
various rodent studies.7–9 In addition, indirect clinical
evidence in humans has been found in patients with
Cushing’s syndrome where elevated cortisol levels are
accompanied by characteristic features of the metabolic
syndrome, that is, visceral obesity, impaired glucose tol-
erance, and hyperglycemia.10 These findings have led to
the hypothesis that selective inhibition of 11b-HSD1
would provide a beneficial therapy against metabolic
syndrome related diseases.11–16
In our ongoing research program on selective 11b-HSD1
inhibitors,17 the piperidinylbenzimidazolone 1 (Ki =
0.30 lM) was identified in a HTS-campaign (Fig. 2).
Based on synthetic accessibility of a wide range of ana-
logs, an expansion of the hit was performed aimed at
improving in vitro potency. The inhibitory properties
of the molecules were evaluated in a SPA-based human
11b-HSD1 enzymatic binding assay.18
Keywords: 11b-HSD1 inhibitors; Piperidine amides; Metabolic
syndrome.
It was found that isosteric alternatives to the piperidine
amide functionality, for example, sulfonamides, ureas or
carbamates, gave decreased 11b-HSD1 binding poten-
cies. Therefore, it was decided to retain the piperidine
*
Corresponding author. Tel.: +47 8 6972865; fax: +46 8 697
2320; e-mail: katarina.flyren@biovitrum.com
Present address: Bio Pte Ltd., 1 Science Park Road, #05-09 The
Capricorn, Singapore Science Park II, Singapore.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.03.083

´
K. Flyren et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3421–3425
3422
Table 1. Inhibitory activities of selected compounds
O
O
R
N
O
N
N
O
N
N
H
O
N
H
Figure 2. HTS hit compound 1.
Compound
R
Human 11b-HSD1 SPA Ki (lM)
amide moiety as featured in 1 and to focus the investiga-
tions on synthetic analogs to the 3-methoxybenzoyl
group as well as substitutions/variations on the benzim-
idazolone ring system.
1
0.30
O
2
3
4
>10
>10
>10
To determine the SAR around the N-acyl substituent at
the piperidyl nitrogen, a series of aryl, heteroaryl, satu-
rated cyclic, and aliphatic piperidine amides were syn-
thesized from commercially available 1-piperidin-4-yl-
1,3-dihydro-2H-benzimidazol-2-one and acyl chlorides
or carboxylic acids (Scheme 1). The 11b-HSD1 SPA
binding assay results of representative examples of these
compounds are shown in Table 1.
O
Cl
5
6
0.45
0.10
N
O
Compounds with aliphatic substituents (2 and 3) were
>10 lM in the SPA assay, and attempts to introduce
alternative heterocycles such as furan (4) also resulted
in poor binding, although the 2-chloro-4-methoxypyri-
dine derivative 5 retained activity. Electron-rich meta-,
para-disubstituted aromatic amides appeared more fa-
vored (6–10), and the most potent compounds (6 and
7) showed a threefold increase in potency when com-
pared to the hit compound 1. Phenyl groups containing
electron-withdrawing substituents such as fluorine (13
and 14) and trifluoromethyl (15–17) gave, on the other
hand, reduced activity. To confirm selectivity, com-
pound 7 was tested against 11b-HSD2 and showed very
weak activity (Ki > 10 lM).
7
8
0.11
0.18
0.50
1.1
O
NH2
O
9
O
O
10
11
12
13
O
Synthetic variations on the benzimidazole scaffold are
described in Schemes 2–5. For comparison purposes,
and since 7 was one of the most potent compounds in
Table 1, the 3-methoxy-4-methylbenzoyl moiety was re-
tained as the piperidyl N-acyl substituent in all of these
compounds. Synthesis of the benzoxazolone 18 was
achieved in four steps from N-Boc-4-piperidone
(Scheme 2). Reductive amination with 2-aminophenol
and sodium triacetoxyborohydride in DCE at room
1.1
1.6
1.7
F
14
15
16
17
3.5
2.6
3.1
1.3
O
R
H
F
N
N
CF3
CF3
a or b
N
N
O
O
N
H
N
H
1−17
Scheme 1. Reagents and conditions: (a) RCOCl, 10% NaOH (aq),
16 h, rt; (b) RCOOH, EDC, Et3N, DCM, rt.
CF3

´
K. Flyren et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3421–3425
3423
O
Boc
N
H
Boc
N
N
N
O
a
b, c
d
N
O
NH
OH
N
O
O
O
O
18
Scheme 2. Reagents and conditions: (a) 2-aminophenol, DCE, NaBH(OAc)3, rt; (b) pyridine, THF, triphosgene, 60 °C; (c) HCl, 50 °C; (d)
3-methoxy-4-methylbenzoic acid, EDC, Et3N, DCM, rt.
Bn
O
N
H
Bn
N
N
N
O
b, c
a
d
O
NH
N
O
N
NH2
O
Br
19
Scheme 3. Reagents and conditions: (a) 2-bromophenylacetyl chloride, K2CO3, MeCN, rt; (b) phenylboronic acid, X-Phos, Pd(OAc)2, K2CO3,
tBuOH, 85 °C, 2 h; (c) ammonium formate, Pd/C, MeOH, MW, 140 °C, 3 min; (d) 3-methoxy-4-methylbenzoic acid, EDC, Et3N, DCM, rt,
overnight.
pyridine as previously described.19 Deprotection with
concentrated HCl and subsequent amide formation
using EDC and Et3N gave the desired benzoxazolone
18.
O
H
N
O
N
O
O
a
b
N
N
S
Br
The synthesis of the indolone 19 was performed in four
steps, the first being acylation of 4-amino-1-benzylpi-
peridine with 2-bromophenylacetyl chloride (Scheme
3). Subsequent ring closure with Pd(OAc)2, PhB(OH)2,
X-Phos, and K2CO3 yielded the benzyl protected
1-(4-piperidyl)indolone.20 Benzyl deprotection with
ammonium formate and Pd/C in MeOH under micro-
wave irradiation and subsequent EDC-catalyzed amide
formation with triethylamine gave the desired target
compound 19.
O
Br
20
Scheme 4. Reagents and conditions: (a) 3-methoxy-4-methylbenzoic
acid, EDC, Et3N, DCM, rt; (b) 2-hydroxybenzothiazole, K2CO3,
90 °C.
temperature overnight yielded the corresponding 2-[1-
Boc-piperidine-4-yl-amino]phenol. Ring-closure to the
benzoxazolidinone was achieved with triphosgene and
O
O
O
O
O
H
N
O
N
N
N
O
b
c
a
N
O
NH
O
N
X
X
NH2
Y
Z
Y
21 X=H, Y=Me, Z=H
22 X=Me Y= Me, Z=H
23 X=F, Y=H, Z=H
7 X=H, Y=H, Z=H
25 X=H, Y=H, Z=Me
24 X=Cl, Y=H, Z=H
26 X=Cl, Y=H, Z=Me
d
d
Scheme 5. Reagents and conditions: (a) 3-methoxy-4-methylbenzoic acid, EDC, Et3N, DCM, rt; (b) X,Y-aryl substituted o-phenylenediamine,
NaBH(OAc)3, AcOH, DCE rt; (c) DSC, MeCN, rt; (d) NaH, MeI, THF, 0 °C.

´
K. Flyren et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3421–3425
3424
Table 2. Inhibitory activities of selected compounds
to Scheme 1. Alkylation of compounds 7 and 24 using
NaH in dry THF followed by addition of excess MeI
yielded the N-methylated benzimidazolones 25 and 26,
respectively.
O
N
O
Table 2 illustrates the variations of the benzimidazolone
scaffold where the SAR was found to be relatively flat in
comparison to the dramatic shifts in activity observed
when altering the N-acyl substituent at the piperidyl
nitrogen. Changing the peripheral scaffold from benzim-
idazolone (7) to the corresponding benzoxazolone (18),
indolone (19), or benzothiazolone (20) gave essentially
equipotent compounds. Various substitution patterns
on the benzimidazolone were tolerated (21–24) but
did not improve potency; however, monosubstituted
benzimidazolone 21 appeared more favored than the
disubstituted derivative 22. N-Methylation of the
benzimidazole (25 and 26) gave compounds with similar
or slightly improved activities when compared to their
non-alkylated analogs (7 and 24). Thus, none of the per-
formed modifications on the benzimidazolone scaffold
resulted in an increase in inhibitory activity when com-
pared to compound 7.
R
Compound
R
Human 11b-HSD1
SPA Ki (lM)
N
O
18
0.27
0.24
0.17
O
N
19
20
O
O
N
S
N
O
21
22
23
0.14
0.33
0.20
N
H
In conclusion, we have identified a novel class of
piperidine amide inhibitors of the human 11b-HSD1
enzyme. Modification of the hit compound 1 resulted
in a threefold increase in potency (compounds 6 and 7).
Alternatives to the piperidine amide linker, variations
of the N-acyl substituent, and substitutions/variations
on the benzimidazolone moiety of 1 were investigated.
N
O
N
H
N
O
N
F
H
Acknowledgments
N
24
25
26
0.50
0.18
0.36
O
N
H
We thank Lars Hammarstro¨m at Biovitrum for help and
discussions during the preparation of this manuscript.
Cl
N
N
O
References and notes
N
N
1. Walker, B. R.; Seckl, J. R. Exp. Opin. Ther. Targets 2003,
7, 771.
2. Fotsch, C.; Askew, B. C.; Chen, J. J. Exp. Opin. Ther.
Patents 2005, 15, 289.
O
Cl
3. Barf, T.; Williams, M. Drugs Future 2006, 31, 231.
4. Kataoka, S.; Kudo, A.; Hirano, H.; Kawakami, H.;
Kawano, T.; Higashihara, E.; Tanaka, H.; Delarue, F.;
Sraer, J.-D.; Mune, T.; Krozowski, Z. S.; Yan, K. J. Clin.
Endocrinol. Metab. 2002, 87, 877.
The corresponding benzothiazolone 20 was synthesized
by coupling of 4-bromopiperidine and 3-methoxy-4-
methylbenzoic acid followed by alkylation of 2-hydroxy-
benzothiazole with potassium carbonate21 to give the
desired product according to Scheme 4.
5. Hanson, R. W.; Reshef, L. Ann. Rev. Biochem. 1997, 66,
581.
Amide coupling of piperidone and 3-methoxy-4-methyl-
benzoic acid using EDC and Et3N in dichloromethane
(DCM) yielded the desired N-acyl piperidone amide
intermediate (Scheme 5). Reductive amination with
aryl-substituted o-phenylenediamines, NaBH(OAc)3,
and AcOH in DCE at room temperature gave the corre-
sponding benzimidazolones. Ring-closure was achieved
using disuccinimido carbonate (DSC) in MeCN at ambi-
ent temperature to give compounds 21–23 in >80% reg-
ioisomeric purity.22 Compound 24 was synthesized
directly from commercially available 5-chloro-1-piperi-
din-4-yl-1,3-dihydro-2H-benzimidazol-2-one according
6. Bujalska, I. J.; Kumar, S.; Hewison, M.; Stewart, P. M.
Endocrinology 1999, 140, 3188.
7. Kotelevtsev, Y.; Holmes, M. C.; Burchell, A.; Houston, P.
M.; Schmoll, D.; Jamieson, P.; Best, R.; Brown, R.;
Edwards, C. R. W.; Seckl, J. R.; Mullins, J. J. Proc. Natl.
Acad. Sci. U.S.A. 1997, 94, 14924.
8. Masuzaki, H.; Paterson, J.; Shinyama, H.; Morton, N. M.;
Mullins, J. J.; Seckl, J. R.; Flier, J. S. Science 2001, 294,
2166.
9. Alberts, P.; Engblom, L.; Edling, N.; Forsgren, M.;
¨
Klingstro¨m, G.; Larsson, C.; Ro¨nquist-Nii, Y.; Ohman,
´
B.; Abrahmsen, L. Diabetologia 2002, 45, 1528.
10. Ross, E. J.; Linch, D. C. Lancet 1982, 2, 646.

´
K. Flyren et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3421–3425
3425
11. Wang, M. Curr. Opin. Invest. Drugs 2006, 7, 319.
12. Xiang, J.; Ipek, M.; Suri, V.; Massefski, W.; Pan, N.; Ge,
Y.; Tam, M.; Xing, Y.; Tobin, J. F.; Xu, X.; Tam, S.
Bioorg. Med. Chem. Lett. 2005, 15, 2865.
St. Jean, D.; Han, N.; Huang, Q.; Liu, Q.; Bartberger, M.
D.; Moniz, G. A.; Frizzle, M. J. WO 05116002, 2005.
18. Human 11b-HSD1 Scintillation Proximity Assay (SPA)
was carried out in triplicate, each replica containing 10 lL
of diluted compound (from a 3-fold dilution series), 50 lL
assay buffer, and 25 lL substrate mixture [3H]-Cortisone /
NADPH (175 nM/200 lM). Reactions were initiated by
the addition of 25 lL of purified Escherichia coli derived
human 11b-HSD1 (40–60 nM final concentration, depend-
ing on the batch). Following mixing, the plates were
incubated on a shaker for 30–60 min at room temperature.
The reactions were terminated with 10 lL stop solution
(1 mM 18b-glycyrrhetinic acid in ethanol). Monoclonal
mouse anticortisol antibody was then added (10 lL of
1.92 lM working solution) followed by 50 lL of YSi SPA
beads coated with monoclonal antimouse antibodies. As
reference substance, carbenoxolone was run in each plate.
The plates were sealed with plastic film (Perkin Elmer, Top
Seal-A) and incubated on a shaker for 30 min at rt before
counting. The amount of [3H]-cortisol captured on the
beads was determined in a microplate liquid scintillation
counter. Kinetic constants were calculated employing the
Microsoft Excel integrated application XLfit (Version
5.3.0.19, ID Business Solutions Ltd.) using the sigmoidal
dose–response model 205 which is based on the non-linear
curve fitting based on Levenberg–Marquardts algorithm.
19. Nerenberg, J. B.; Erb, J. M.; Thompson, W. J.; Lee, H.-Y.;
Guare, J. P.; Munson, P. M.; Bergman, J. M.; Huff, J. R.;
Broten, T. P.; Chang, R. S. L.; Chen, T. B.; O’Malley, S.;
Schorn, T. W.; Scott, A. L. Bioorg. Med. Chem. Lett.
1998, 8, 2467.
13. Olson, S.; Aster, S. D.; Brown, K.; Carbin, L.; Graham,
D. W.; Hermanowski-Vosatka, A.; LeGrand, C. B.;
Mundt, S. S.; Robbins, M. A.; Schaeffer, J. M.; Slossberg,
L. H.; Szymonifka, M. J.; Thieringer, R.; Wright, S. D.;
Balkovec, J. M. Bioorg. Med. Chem. Lett. 2005, 15, 4359;
Gu, X.; Dragovic, J.; Koo, G. C.; Koprak, S. L.;
LeGrand, C.; Mundt, S. S.; Shah, K.; Springer, M. S.;
Tan, E. Y.; Thieringer, R.; Hermanowski-Vosatka, A.;
Zokian, H. J.; Balkovec, J. M.; Waddell, S. T. Bioorg.
Med. Chem. Lett. 2005, 15, 5266.
14. Coppola, G. M.; Kukkola, P. J.; Stanton, J. L.; Neubert,
A. D.; Marcopulos, N.; Bilci, N. A.; Wang, H.; Tomaselli,
H. C.; Tan, J.; Aicher, T. D.; Knorr, D. C.; Jeng, A. Y.;
Dardik, B.; Chatelain, R. E. J. Med. Chem. 2005, 48, 6696.
15. Su, X.; Vicker, N.; Ganeshapillai, D.; Smith, A.; Purohit,
A.; Reed, M. J.; Potter, B. V. L. Mol. Cell. Endocrinol.
2006, 248, 214.
16. Rohde, J. J.; Pliushchev, M. A.; Sorensen, B. K.; Wodka,
D.; Shuai, Q.; Wang, J.; Fung, S.; Monzon, K. M.;
Chiou, W. J.; Pan, L.; Deng, X.; Chovan, L. E.;
Ramaiya, A.; Mullally, M.; Henry, R. F.; Stolarik, D.
F.; Imade, H. M.; Marsh, K. C.; Beno, D. W. A.; Fey, T.
A.; Droz, B. A.; Brune, M. E.; Camp, H. S.; Sham, H.
L.; Frevert, E. U.; Jacobson, P. B.; Link, J. T. J. Med.
Chem. 2007, 50, 149.
˚
17. Barf, T.; Vallgarda, J.; Emond, R.; Ha¨ggstrom, C.; Kurz,
G.; Nygren, A.; Larwood, V.; Mosialou, E.; Axelsson, K.;
Olsson, R.; Engblom, L.; Edling, N.; Ronquist-Nii, Y.;
Ohman, B.; Alberts, P.; Abrahmsen, L. J. Med. Chem.
2002, 45, 3813; Henriksson, M.; Homan, E.; Johansson,
˚
L.; Vallgarda, J.; Williams, M.; Bercot, E.; Fotsch, C. H.;
Li, A.; Cai, G.; Hungate, R. W.; Yuan, C. C.; Tegley, C.;
20. van den Hoogenband, A.; den Hartog, J. A. J.; Lange, J.
H. M.; Terpstra, J. W. Tetrahedron Lett. 2004, 45, 8535.
21. D’Amico, J. J.; Bollinger, F. G. J. Heterocycl. Chem. 1988,
25, 1487.
22. Takeda, K.; Ogura, H. Synth. Commun. 1982, 12, 213.