N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275

Article abstract of DOI:10.1016/j.bmcl.2009.05.011

N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.

Full text of DOI:10.1016/j.bmcl.2009.05.011

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3493–3497
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11b-hydroxysteroid
dehydrogenase type 1: Discovery of PF-915275
a
a
a
a
Michael Siu a, , Theodore O. Johnson , Yong Wang , Sajiv K. Nair , Wendy D. Taylor ,
Stephan J. Cripps a, Jean J. Matthews a, Martin P. Edwards a, Thomas A. Pauly b, Jacques Ermolieff c,
Arturo Castro c, Natilie A. Hosea d, Amy LaPaglia d, Andrea N. Fanjul e, Jennifer E. Vogel e
*
a Discovery Chemistry, Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States
b Structural and Computational Biology and Design, Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States
c Biochemical Pharmacology, Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States
d Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States
e Diabetes Biology, Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 February 2009
Revised 3 May 2009
Accepted 4 May 2009
Available online 7 May 2009
N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11b-hydroxysteroid dehydrogenase type
1 (11bHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysreg-
ulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syn-
drome. In this Letter, we present the development of an initial lead to an efficient ligand with
improved physiochemical properties using a deletion strategy. This strategy allowed for further optimi-
zation of potency leading to the discovery of the clinical candidate PF-915275.
Keywords:
11-b-Hydroxysteroid dehydrogenase
PF-915275
Ó 2009 Elsevier Ltd. All rights reserved.
Diabetes
Lipophilic efficiency
11b-Hydroxysteroid dehydrogenase type 1 (11bHSD1), a short
chain reductase expressed mainly in the adipose and the liver, cat-
alyzes the reduction of the inactive glucocorticoid cortisone to the
active glucocorticoid cortisol using the cofactor NADPH (Fig. 1).
Dysregulation of glucocorticoids in the liver and adipose has been
implicated in the pathogenesis of diabetes and the metabolic syn-
drome.1 Cortisol is involved in metabolic and homeostatic path-
ways, one of which is gluconeogenesis in the liver. In non-insulin
dependent diabetes mellitus, gluconeogenesis can contribute up
to 90% of the increase in overall hepatic glucose production.2 The
been disclosed by others.4,5 We present in this communication our
efforts toward developing an efficient inhibitor of 11bHSD1 leading
to the discovery of clinical candidate PF-915275.
OH
OH
OH
OH
O
H3C
O
H3C
11βHSD1
NADPH
O
HO
H3C
H3C
11βHSD2
type
2 isoform, 11b-hydroxysteroid dehydrogenase type 2
NAD
(11bHSD2), is expressed mainly in the kidney and catalyzes the re-
verse reaction (oxidation of cortisol to cortisone) to prevent activa-
tion of the mineralcorticoid receptor by cortisol. Interest in the
inhibition of 11bHSD1 has emerged because of the potential to
control cortisol concentrations in the liver and adipose without
affecting systemic circulating concentrations. In 2002 Barf et al. re-
ported 2-aminothiazole sulfonamides as the first selective
11bHSD1 inhibitors.3 Subsequently, various potent inhibitors have
O
O
cortisone
(inactive glucocorticoid)
cortisol
(active glucocorticoid)
Figure 1. Interconversion between cortisone and cortisol mediated by 11bHSD1
and 11bHSD2.
Ki = 0.287 μM
H3C
O
O O
S
HLM = high CL
Caco2 BA = 12 x 10-6 cm/s
Caco2 AB = 20 x 10-6 cm/s
ClogP = 2.91
Cl
N
N
N
CH3
CH3
H
* Corresponding author at present address: Genentech, Inc., 1 DNA Way, MS 18B,
South San Francisco, CA 94080, United States. Tel.: +1 650 467 7764; fax: +1 650
467 8922.
Binding Efficiency
= 0.33 kcal/mol/atom
1
E-mail address: siu.michael@gene.com (M. Siu).
Figure 2. Initial lead.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.05.011

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M. Siu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3493–3497
Our initial lead, N-(pyridin-2-yl) benzenesulfonamide 1, has a Ki
of 0.287
M against 11bHSD1 (Fig. 2).6 Although reasonably potent
l
in our biochemical assay, the sulfonamide 1 has poor in vitro phar-
macokinetic properties. In particular, sulfonamide 1 is categorized
as a high clearance compound in our in vitro human liver micro-
some assay. Close-in analogs of amide 1, shown in Table 1, did
not have significantly improved potency.
In addition to potency, we sought to improve the physiochem-
ical properties of sulfonamide 1. Accordingly, a deletion strategy
was employed to reduce molecular weight, hydrogen bond accep-
tors and rotatable bonds. Tactical implementation included re-
moval of the amide functional group. A cocrystal structure of
sulfonamide 1 bound to guinea pig 11bHSD1 with NADP shows
the ethyl groups of the diethylamide substituent positioned in a
polar region of the protein with several unsatisfied hydrogen bond
donors and acceptors. This observation suggested that the diethyl
amide may be too lipophilic for this region of the protein, and that
truncation may not compromise potency (Fig. 3).7
Figure 3. X-ray cocrystal structure of compound 1 (blue) and NADP (magenta)
bound to guinea pig 11bHSD1 (green).
O
H3C
O
Representative chemistry that enabled the synthesis of the
amides in Table 1 is shown in Scheme 1.8 Sulfonylation of amino-
pyridine 9, derived from commercially available 2-amino-6-meth-
ylpyridine,9 with 3-chloro-2-methylbenzenesulfonyl chloride in
pyridine provided ester 10. Direct amide formation occurred upon
treatment of intermediate 10 with chloromethylaluminum mor-
pholide (CH2Cl2, 0?24 °C) to afford amide 2.10
In keeping with our deletion strategy, 2-amino-6-methylpyri-
dine 11 was then synthesized.11 Removal of the diethylamide re-
sulted in a lower molecular weight compound with improved
potency, ligand binding efficiency,12 in vitro metabolic stability,
and permeability (Fig. 4).
Although compound 11 revealed new structure–activity rela-
tionship findings at the pyridyl C-6 position and provided im-
proved potency and stability compared to the initial lead (1), the
potency was still below our laboratory objectives. With a view to
further enhancing the potency of 11, we investigated substitution
O O
S
a
Cl
H2N
N
OEt
N
N
OEt
H
9
10
b
H3C
O
O O
S
Cl
N
H
N
N
O
2
Scheme 1. Reagents and conditions: (a) 3-chloro-2-methylbenzenesulfonyl chlo-
ride, pyridine, 75%; (b) (CH3)2AlCl, morpholine, CH2Cl2, 0?24 °C, 96%.
Ki = 0.169 uM
H3C
O O
S
HLM = low CL
Caco2 AB = 36 x 10-6 cm/s
Caco2 BA = 46 x 10-6 cm/s
ClogP = 3.53
Cl
N
N
CH3
H
Table 1
Binding Efficiency
11
= 0.44 kcal/mol/atom
H3C
O
O O
S
Cl
Figure 4. Compound 11 properties.
N
N
R
H
on the phenylsulfonamide. A survey of aryl groups on the sulfonyl
group (Table 2) showed that electron deficient aromatic groups
that maximize pi–pi interaction to an adjacent tyrosine improved
potency (see Fig. 3), although the substitution pattern was impor-
tant (e.g., 12 vs 13). The largest initial gain in enzymatic potency
was obtained when a biphenyl substitution (18) was evaluated
wherein the binding affinity improved to <50 nM. Biphenylsulfona-
mide 18 provided a fourfold enhancement in potency in compari-
son to 11 but lacked metabolic stability as expected due to the
increased lipophilicity. Further evaluation of groups on the biaryl
appendage showed that electron withdrawing groups such as
fluoro and cyano at the 40-position provided significant improve-
ments in potency and metabolic stability with the 40-cyanobiphe-
nyl substitution (22) being the most optimal.
Further optimization of this series was achieved by maintaining
the 40-cyanobiphenyl group and varying the 6-position on the pyr-
idine ring. We began this exploration by reviewing additional alkyl
groups in place of the methyl group in 22, such as the ethyl, cyclo-
propyl and iso-propyl groups (compounds 23–25, Table 3). These
alkyl substituents either retained or showed slight improvements
in potency. In contrast, the introduction of an amino substitution
(26, PF-915275) provided a considerable gain in activity while
reducing lipophilicity (Clog P = 2.76) thus improving lipophilicity
R
11bHSD1 % inhib @ 0.1
lM
11bHSD1 Ki (nM)
1
2
3
4
5
6
7
8
—
287
6
—
55
8
169
—
39
22
11
25
—
—
—
—

M. Siu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3493–3497
3495
Table 2
Table 3
O O
S
O O
S
N
N
R
Ar
N
N
CH3
H
H
Ar
11bHSD1 % inhib
11bHSD1
Ki (nM)
NC
@ 0.1
lM
R
11bHSD1 Ki (nM)
11bHSD1 HEK293 EC50 (nM)
H3C
23
24
25
CH3
CH3
6.6
40
Cl
11
12
—
169
108
1.9
1.7
50
5
—
F3C
CH3
F3C
13
14
1
—
—
26
27
28
29
<1.0
9.8
5
NH2
CH3
23
184
10
N
H
H3CO
N
H
CH3
4.8
15
16
17
18
19
20
21
22
32
46
10
52
87
96
84
99
—
t-Bu
CH3
N
ND
846
CH3
84
—
PF-915275 (26) maintains potency in our cellular assay against
human 11bHSD1 (HEK293, EC50 = 5 nM) and is selective against
human 11bHSD2 (HEK293, 1.5% inhibition 10
M).13 PF-
915275, in general, displayed only weak affinity for the rodent cho-
line transporter (Ki = 9.6 M) and the hamster melatonin MT3
receptor (Ki = 9.6 M) in the Cerep Bioprint screening panel. PF-
915275 (26) has good in vitro pharmacokinetic properties. In par-
ticular, 26 is categorized as a low clearance compound (liver
microsome assays) with high permeability (Caco2 assay). As a pre-
lude to in vivo studies with PF-915275 (26), the rat pharmacoki-
netic properties of this compound were determined. As shown in
Table 4, PF-915275 (26) has an excellent pharmacokinetic profile
characterized by low clearance, long half-life and good oral
bioavailability.
The favorable potency and pharmacokinetic profile of PF-915275
(26) led us to progress this compound into an in vivo model to quan-
tify the relationship between 11bHSD1 inhibition and exposure (PK/
PD). As noted above, this sulfonamide is a selective and potent inhib-
itor of the human 11bHSD1 enzyme. On evaluating the cross-species
potency of PF-915275 (26), it was found to be significantly less
active against the mouse 11bHSD1 enzyme (Ki = 750 nM). The
difference between human and rodent species was also observed
in rat hepatoma cells (EC50 = 14,500 nM). Thus, PF-915275 (26)
@
l
l
l
48
20
5.8
62
4
F
Cl
H3C
NC
Table 4
Compound
CLp
Vss
T1/2
AUC(oral)
F
*
(mL/min/kg)
(L/kg)
(h)
(h
l
g/mL)
PF-915275 (26)
0.87
0.38
6.6
14.7
74%
efficiency. A review of alkylamino substitutions (compounds 27–
29) highlighted the importance of having an unsubstituted amino
group for potency.
IV = 0.1 mg/kg; 40% PEG200, 10% ethanol, 50% H2O.
PO = 1 mg/kg; 0.5% methyl cellulose suspension.

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M. Siu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3493–3497
2. Consoli, A.; Nurjhan, N.; Capani, F.; Gerich, J. Diabetes 1989, 38, 550.
O
a
3. Barf, T.; Vallgårda, J.; Emond, R.; Häggstroem, C.; Kurz, G.; Nygren, A.; Larwood,
V.; Mosialou, E.; Axelsson, K.; Olsson, R.; Engblom, L.; Edling, N.; Rönquist-Nii,
Y.; Öhman, B.; Alberts, P.; Abrahmsén, L. J. Med. Chem. 2002, 45, 3813.
4. (a) 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; (b) 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; (c) 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; (d) 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; (e) Yeh, V. S. C.; Kurukulasuriya, R.; Madar, D.; Patel, J. R.; Fung, S.;
Monzon, K.; Chiou, W.; Wang, J.; Jacobson, P.; Sham, H. L.; Link, J. T. Bioorg. Med.
Chem. Lett. 2006, 16, 5408; (f) Yeh, V. S. C.; Patel, J. R.; Yong, H.; Kurukulasuriya,
R.; Fung, S.; Monzon, K.; Chiou, W.; Wang, J.; Stolarik, D.; Imade, H.; Beno, D.;
Brune, M.; Jacobson, P.; Sham, H.; Link, J. T. Bioorg. Med. Chem. Lett. 2006, 16,
5414; (g) Yeh, V. S. C.; Kurukulasuriya, R.; Fung, S.; Monzon, K.; Chiou, W.;
Wang, J.; Stolarik, D.; Imade, H.; Shapiro, R.; Knourek-Segel, V.; Bush, E.;
Wilcox, D.; Nguyen, P. T.; Brune, M.; Jacobson, P.; Link, J. T. Bioorg. Med. Chem.
Lett. 2006, 16, 5555; (h) Sorensen, B.; Rohde, J.; Wang, J.; Fung, S.; Monzon, K.;
Chiou, W.; Pan, L.; Deng, X.; Stolarik, D.; Frevert, E. U.; Jacobson, P.; Link, J. T.
Bioorg. Med. Chem. Lett. 2006, 16, 5958; (i) Richards, S.; Sorensen, B.; Jae, H.;
Winn, M.; Chen, Y.; Wang, J.; Fung, S.; Monzon, K.; Frevert, E. U.; Jacobsen, P.;
Link, J. T. Bioorg. Med. Chem. Lett. 2006, 16, 6241; (j) St. Jean, D. J., Jr.; Yuan, C.;
Bercot, E. A.; Cupples, R.; Chen, M.; Fretland, J.; Hale, C.; Hungate, R. W.;
Komorowski, R.; Veniant, M.; Wang, M.; Zhang, X.; Fotsch, C. J. Med. Chem.
2007, 50, 429; (k) Rodhe, 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.
J. Med. Chem. 2007, 50, 149; (l) Sorensen, B.; Winn, M.; Rohde, J.; Shuai, Q.;
Wang, J.; Fung, S.; Monzon, K.; Chiou, W.; Stolarik, D.; Imade, H.; Pan, L.; Deng,
X.; Chovan, L.; Longenecker, K.; Judge, R.; Qin, W.; Brune, M.; Camp, H.; Frevert,
E. U.; Jacobson, P.; Link, J. T. Bioorg. Med. Chem. Lett. 2007, 17, 527; (m) Patel, J.
R.; Shuai, Q.; Dinges, J.; Winn, M.; Pliushchev, M.; Fung, S.; Monzon, K.; Chiou,
W.; Wang, J.; Pan, L.; Wagaw, S.; Engstrom, K.; Kerdesky, F. A.; Longenecker, K.;
Judge, R.; Qin, W.; Imade, H. M.; Stolarik, D.; Beno, D. W. A.; Brune, M.; Chovan,
L. E.; Sham, H. L.; Jacobsen, P.; Link, J. T. Bioorg. Med. Chem. Lett. 2007, 17, 750;
(n) Webster, S. P.; Ward, P.; Binnie, M.; Craigie, E.; McConnell, K. M. M.; Sooy,
K.; Vinter, A.; Seckl, J. R.; Walker, B. R. Bioorg. Med. Chem. Lett. 2007, 17, 2838;
(o) Flyrén, K.; Bergquist, L. O.; Castro, V. M.; Fotsch, C.; Johansson, L.; St. Jean, D.
J., Jr.; Sutin, L.; Williams, M. Bioorg. Med. Chem. Lett. 2007, 17, 3421; (p) Xiang, J.;
Ipek, M.; Suri, V.; Tam, M.; Xing, Y.; Huang, N.; Zhang, Y.; Tobin, J.; Mansour, T.
S.; McKew, J. Bioorg. Med. Chem. 2007, 15, 4396; (q) Sutin, L.; Andersson, S.;
Bergquist, L.; Castro, V. M.; Danielsson, E.; James, S.; Henriksson, M.; Johansson,
L.; Kaiser, C.; Flyrén, K.; Williams, M. Bioorg. Med. Chem. Lett. 2007, 17, 4837; (r)
Yuan, C.; St. Jean, D. J., Jr.; Liu, Q.; Cai, L.; Li, A.; Han, N.; Moniz, G.; Askew, B.;
Hungate, R. W.; Johansson, L.; Tedenborg, L.; Pyring, D.; Williams, M.; Hale, C.;
Chen, M.; Cupples, R.; Zhang, J.; Jordan, S.; Bartberger, M. D.; Sun, Y.; Emery, M.;
Wang, M.; Fotsch, C. Bioorg. Med. Chem. Lett. 2007, 17, 6056; (s) Aster, S. D.;
Graham, D. W.; Kharbanda, D.; Patel, G.; Ponpipom, M.; Santorelli, G. M.;
Szymonifka, M. J.; Mundt, S. S.; Shah, K.; Springer, M. S.; Thieringer, R.;
Hermanowski-Vosatka, A.; Wright, S. D.; Xiao, J.; Zokian, H.; Balkovec, J. M.
Bioorg. Med. Chem. Lett. 2008, 18, 2799; (t) Johansson, L. et al J. Med. Chem. 2008,
51, 2933; (u) Wang, H.; Ruan, Z.; Li, J. J.; Simpkins, L. M.; Smirk, R. A.; Wu, S. C.;
Hutchins, R. D.; Nirschl, D. S.; Kirk, K. V.; Cooper, C. B.; Sutton, J. C.; Ma, Z.;
Golla, R.; Seethala, R.; Salyan, M. E. K.; Nayeem, A.; Krystek, S. R., Jr.; Sheriff, S.;
Camac, D. M.; Morin, P. E.; Carpenter, B.; Robl, J. A.; Zahler, R.; Gordon, D. A.;
Hamann, L. G. Bioorg. Med. Chem. Lett. 2008, 18, 3168; (v) Zhu, Y.; Olson, S. H.;
Hermanowski-Vosatka, A.; Mundt, S.; Shah, K.; Springer, M.; Thieringer, R.;
Wright, S.; Xiao, J.; Zokian, H.; Balkovec, J. M. Bioorg. Med. Chem. Lett. 2008, 18,
3405; (w) Zhu, Y.; Olson, S. H.; Graham, D.; Patel, G.; Hermanowski-Vosatka, A.;
Mundt, S.; Shah, K.; Springer, M.; Thieringer, R.; Wright, S.; Xiao, J.; Zokian, H.;
Dragovic, J.; Balkovec, J. M. Bioorg. Med. Chem. Lett. 2008, 18, 3412; (x) Sun, D.;
Wang, Z.; Di, Y.; Jaen, J. C.; Labelle, M.; Ma, J.; Miao, S.; Sudom, A.; Tang, L.;
Tomooka, C. S.; Tu, H.; Ursu, S.; Walker, N.; Yan, X.; Ye, Q.; Powers, J. P. Bioorg.
Med. Chem. Lett. 2008, 18, 3513; (y) Julian, L. D.; Wang, Z.; Bostick, T.; Caille, S.;
Choi, R.; DeGraffenreid, M.; Di, Y.; He, X.; Hungate, R. W.; Jaen, J. C.; Liu, J.;
Monshouwer, M.; McMinn, D.; Rew, Y.; Sudom, A.; Sun, D.; Tu, H.; Ursu, S.;
Walker, N.; Yan, X.; Ye, Q.; Powers, J. P. J. Med. Chem. 2008, 51, 3953; (z) Xiang,
J.; Wan, Z.; Li, H.; Ipek, M.; Binnun, E.; Nunez, J.; Chen, L.; McKew, J. C.;
Mansour, T. S.; Xu, X.; Suri, V.; Tam, M.; Xing, T.; Li, X.; Hahm, S.; Tobin, J.;
Saiah, E. J. Med. Chem. 2008, 51, 4068.
H2N
N
N
Ot-Bu
H2N
N
NH2
H
c
30
32
O O
S
Cl
b
NC
NC
31
33
O
O O
S
d
N
H
N
N
Ot-Bu
H
26
NC
34
Scheme 2. Reagents and conditions: (a) LiHMDS, BOC2O, THF, 42%; (b) (i) ClSO3H,
CH2Cl2, 10 °C, (ii) NaOH, (iii) POCl3, 106 °C, 40%; (c) pyridine; (d) HCl, dioxane, 70 °C,
54% (from 32).
demonstrated species-dependent potency in both our biochemical
and cellular assays, and its activity in primary hepatocytes can be
rank ordered as human (EC50 = 20 nM) > monkey (EC50 = 100 nM) >
dog (EC50 = 120 nM). The lack of rodent enzyme inhibitory activity
presented a situation wherein PF-915275 (26) could not be used to
demonstrate biomarker inhibition or efficacy in rodent models. To
circumvent this issue, the in vivo target inhibition was demon-
strated in primates using prednisone to prednisolone conversion,
in the absence and presence of PF-915275 (26), as a biomarker for
11bHSD1 inhibition.14 This pharmacodynamic approach was
evaluated further in healthy human volunteers in Phase I studies
which also assessed the safety, tolerability and pharmacokinetics
of PF-915275 (26).15
PF-915275 (26) is synthesized in ꢀ22% overall yield over four
steps (longest linear sequence) as shown in Scheme 2. The syn-
thetic route begins with commercially available 2,6-diaminopyri-
dine (30) and 4-cyanobiphenyl (31). Monoprotection of the
diaminopyridine 30 provides the t-butylcarbamate 32. Chlorosulf-
onylation of the 4-cyanobiphenyl (31) afforded the 40-cyanobiphe-
nyl-4-sulfonyl chloride (33). Subsequent coupling of the
aminopyridine 32 and sulfonyl chloride 33 furnished sulfonamide
34, which was deprotected under acidic conditions to afford PF-
915275 (26).
In conclusion, N-(pyridin-2-yl) arylsulfonamides are identified
as inhibitors of 11bHSD1. Implementation of a deletion strategy ar-
rived at efficient inhibitors with improved ligand efficiency and
physiochemical properties. Further optimization furnished clinical
candidate PF-915275 (26), a potent and selective inhibitor of hu-
man 11bHSD1 with good preclinical pharmacokinetic properties.
Acknowledgement
We thank Dr. Simon Bailey and Dr. Paul Rejto for careful review
and helpful discussions regarding this manuscript.
5. Reviews of patent applications: (a) Fotsch, C.; Askew, B.; Chen, J. J. Expert Opin.
Ther. Patent 2005, 15, 289; (b) Webster, S. P.; Pallin, T. D. Expert Opin. Ther.
Patent 2007, 17, 1407.
References and notes
6. Castro, A.; Zhu, J. X.; Alton, G. R.; Rejto, P.; Ermolieff, J. Biochem. Biophys. Res.
Commun. 2007, 357, 561.
7. Protein Data Bank: 3G49
1. (a) Tomlinson, J. W.; Walker, E. A.; Bujalska, I. J.; Draper, N.; Lavery, G. G.;
Cooper, M. S.; Hewison, M.; Stewart, P. M. Endocr. Rev. 2004, 25, 831; (b) Seckl,
J. R.; Walker, B. R. Trends Endocrinol. Metab. 2004, 15, 418; (c) Tomlinson, J. W.;
Stewart, P. M. Drug Discovery Today Ther. Strateg. 2005, 2, 93; (d) Wamil, M.;
Seckl, J. R. Drug Discovery Today 2007, 12, 504.
8. Ethyl [6-(3-chloro-2-methyl-benzenesulfonyl-amino)-pyridin-2-yl]-acetate (10):
3-Chloro-2-methylbenzenesulfonyl chloride (3.4 g, 15 mmol, 1.5 equiv) was
added in one portion to a solution of ethyl 2-(6-aminopyridin-2-yl)acetate (9)
(1.8 g, 10 mmol, 1 equiv) in pyridine (75 mL) at 24 °C. After 16 h, the pyridine

M. Siu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3493–3497
3497
was removed in vacuo (<1 mm Hg), and the resulting residue was dissolved in
ethyl acetate (200 mL). The organic solution was washed sequentially with
water (3 ꢁ 100 mL) and saturated aqueous sodium chloride solution (100 mL).
The collected organic was dried over anhydrous sodium sulfate, filtered, and
concentrated. Purification by high performance flash chromatography (0?5%
methanol in dichloromethane) yielded product (2.76 g, 75%). 1H NMR
(400 MHz, CDCl3), d: 8.02 (dd, J = 8.0, 1.1 Hz, 1H), 7.52 (dd, J = 8.5, 7.4 Hz,
2H), 7.22 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 7.3 Hz, 1H), 4.17
(q, J = 7.1 Hz, 2H), 3.68 (s, 2H), 2.73 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); HRMS (ESI):
Calcd for C16H18ClN2O4S m/z 369.0676; Found: 369.0677.
3-Chloro-2-methyl-N-[6-(2-morpholin-4-yl-2-oxoethyl)-pyridin-2-yl]-benzenesul-
fonamide (2): Dimethylaluminum chloride (1.36 mL, 1.36 mmol, 5.0 equiv, 1.0 M
in hexanes) was added dropwise to an ice-cooled solution of morpholine
(0.119 mL, 1.36 mmol, 5.0 equiv) in dichloromethane (3 mL). The resulting
solution was warmed to 24 °C for 1 h before the addition of a solution of ethyl [6-
(3-chloro-2-methyl-benzenesulfonylamino)-pyridin-2-yl]-acetate (10) (0.100
g, 0.271 mmol, 1 equiv) in dichloromethane (2 mL). After 1 h, 20% sodium
potassium tartrate aqueous solution (5 mL) was slowly added to the reaction
mixture, and the resulting suspension was stirred vigorously for an additional
hour. The resulting mixture was extracted with dichloromethane (2 ꢁ 25 mL).
The collected organic was dried over anhydrous sodium sulfate, filtered, and
concentrated. Purification by high performance flash chromatography (0?10%
methanol in dichloromethane) yielded a light orange solid (0.107 g, 96%). 1H
NMR (400 MHz, CDCl3), d: 8.01 (dd, J = 8.1, 1.0 Hz, 1H), 7.53 (t, J = 8.1 Hz, 2H),
7.23 (m, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 7.3 Hz, 1H), 3.77 (s, 2H), 3.63 (m,
4H), 3.56 (m, 2H). 3.48 (m, 2H), 2.73 (s, 3H); HRMS (ESI): Calcd for C18H21ClN3O4S
m/z: 410.0941; Found: 410.0936.
9. Goto, J.; Sakane, K.; Nakai, Y.; Teraji, T.; Kamiya, T. J. Antibiot. 1984, 37, 532.
10. Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38, 2685.
11. Prepared following the method described for the synthesis of ethyl [6-(3-
chloro-2-methylbenzenesulfonyl-amino)-pyridin-2-yl] acetate (9) using the
appropriate starting materials.
12. Hopkins, A. L.; Groom, C. R.; Alex, A. Drug Discovery Today 2004, 9, 430.
13. Bujalska, I.; Shimojo, M.; Howie, A.; Stewart, P. M. Steroids 1997, 62, 77.
14. Bhat, B. G.; Hosea, N.; Fanjul, A.; Herrera, J.; Chapman, J.; Thalacker, F.; Stewart,
P. M.; Rejto, P. A. J. Pharmacol. Exp. Ther. 2008, 324, 299.
15. Courtney, R.; Stewart, P. M.; Toh, M.; Ndongo, M.; Calle, R. A.; Hirshberg, B. J.
Clin. Endocrinol. Metab. 2008, 93, 550.