N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1: Strategies to eliminate reactive metabolites

Article abstract of DOI:10.1016/j.bmcl.2013.02.066

N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure-activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11β-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay.

Full text of DOI:10.1016/j.bmcl.2013.02.066

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2344–2348
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11b-hydroxysteroid
dehydrogenase type 1: Strategies to eliminate reactive metabolites
a
a
a
a
Sajiv K. Nair a, , Jean J. Matthews , Stephan J. Cripps , Hengmiao Cheng , Jacqui E. Hoffman ,
Christopher Smith a, Stanley Kupchinsky a, Michael Siu a, Wendy D. Taylor a, Yong Wang a,
Theodore O. Johnson a, Klaus R. Dress a, Martin P. Edwards a, Sue Zhou b, Natilie A. Hosea b,
Amy LaPaglia b, Ping Kang b, Arturo Castro c, Jacques Ermolieff c, Andrea Fanjul c, Jennifer E. Vogel c,
Paul Rejto d, Deepak Dalvie b
⇑
a Medicinal Chemistry, Pfizer Global R&D, San Diego, CA 92121, USA
b Pharmacokinetics, Dynamics and Metabolism, Pfizer Global R&D, San Diego, CA 92121, USA
c Biochemical Pharmacology, Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA
d Computational Biology, Pfizer Global R&D, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11b-
hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed
glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to
progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this
series of inhibitors. Based on the proposed mechanism of bioactivation and structure–activity relation-
ships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent
11b-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were
negative in the reactive metabolite assay.
Received 8 December 2012
Revised 7 February 2013
Accepted 13 February 2013
Available online 24 February 2013
Keywords:
11b-Hydroxysteroid dehydrogenase
11b-HSD
PF-915275
Reactive metabolite
Bioactivation
R1
Glutathione adduct
Diabetes
Inhibitor
O
O
O
O
S
S
N
H
N
R
N
H
N
R
NC
NC
1
1
18
20
: R = CH3
: R = NH2, R = CH3
1
2: R = NH2 (PF-915275)
: R = CH2OH, R = H
Ó 2013 Elsevier Ltd. All rights reserved.
Dysregulation of glucocorticoids has been associated with the
pathogenesis of diabetes, metabolic syndrome and age-related
cognitive dysfunction.1 11b-Hydroxysteroid dehydrogenase iso-
zymes (11b-HSD 1 and 2) are microsomal enzymes that mediate
the intracellular metabolism of glucocorticoids. 11b-Hydroxyster-
oid dehydrogenase type 1 (11b-HSD1) is expressed mainly in the
adipose tissue, liver, and in the central nervous system and it cat-
alyzes the reduction of the inactive glucocorticoid cortisone using
the cofactor NADPH. The type 2 isoform, 11b-HSD2, is expressed
mainly in the kidney and catalyzes the oxidation of the active glu-
cocorticoid cortisol to cortisone to prevent activation of the miner-
alocorticoid receptor by cortisol.2 11b-HSD1 mediates the
prereceptor activation of cortisone and thus its inhibition provides
⇑
Corresponding author. Tel.: +1 858 526 4894.
E-mail address: sajiv.k.nair@pfizer.com (S.K. Nair).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.02.066

S. K. Nair et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2344–2348
2345
the ability to control cortisol concentrations at the desired tissues
without affecting systemic circulating concentrations.3 Inhibition
of 11b-HSD1 offers a potential therapy to treat type 2 diabetes4
and numerous 11b-HSD1 inhibitors have been reported in recent
literature.5
As a part of our efforts to discover novel inhibitors of 11b-
hydroxysteroid dehydrogenase type 1 (11b-HSD1), we identified
the N-(pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) as po-
tential clinical candidates (Fig. 1).6 These compounds were selec-
tive and potent inhibitors of the human 11b-HSD1 (1, HEK293
EC50 = 53 nM, 2, HEK293 EC50 = 5 nM) and showed good selectivity
Both compounds also exhibited excellent pharmacokinetic pro-
files in rat, characterized by very low clearance, long half-lives and
good oral bioavailability (Table 1) and were stable towards oxida-
tive metabolism when incubated with human liver microsomes
containing NADPH. However, surprisingly despite their good
ADME properties both 1 and 2 showed a potential to form electro-
philic intermediates which was assessed by their ability to form
glutathione (GSH) adducts when incubated with GSH and NADPH
fortified liver microsomes (see Supplementary data for LC–MS/
MS data of adducts).
Metabolic activation of drugs to electrophilic reactive interme-
diates that covalently bind to macromolecules has been implicated
in idiosyncratic adverse drug reactions. Such drug entities are usu-
ally characterized by the presence of ‘structural alerts’ or toxico-
phores, structural motifs that undergo biotransformation and
give rise to the causative reactive species.7 The element of surprise
in the data obtained from the GSH assay arose from the perceived
absence of such structural alerts in compounds 1 and 2. Based on
the favorable physicochemical properties and cell based potency,
2 was selected as our lead compound for further advancement into
in vivo pharmacodynamic studies.8 Given the need for an exquisite
safety profile for diabetes therapeutics, we deemed it necessary to
assess the risks posed by their metabolic activation. This commu-
nication presents the results of the risk benefit analysis9 of the
reactive metabolite formation and the design efforts undertaken
to circumvent this issue in this class of 11b-HSD1 inhibitors.
As part of our risk benefit analysis for sulfonamide 2, a number
of studies were carried out to assess the impact of the reactive
metabolite findings. In vitro covalent binding studies with 14C-la-
beled 2 (14C-label on nitrile group) showed that non-specific bind-
ing to proteins was reduced to near background levels when 14C-
labeled 2 was incubated with subcellular fractions (liver S9 and
microsomes) of various species in a mixture containing co-factors
against 11b-HSD2 (2, 1.5% inhibition at 10 lM).
O
O
O
O
S
S
N
N
CH3
NC
N
N
NH2
H
H
NC
2 (PF-915275)
1
Figure 1. Lead N-(pyridin-2-yl) arylsulfonamides.
Table 1
Rat pharmacokinetic data for 1 and 2
Cl (mL/min/kg)
Vss (L/kg)
T1/2 (h)
F (%)
1
2
0.06
0.87
0.15
0.38
28
5
89
73a
Dosed at 0.1 mg/kg iv and 0.5 mg/kg p.o.
a
60% When dosed as suspension in 0.5% methylcellulose.
857
900
800
700
A
Rat
600
500
400
300
200
100
Human
218
136
96
40
19
13.3
6.1
0
700
600
500
400
300
200
100
0
633
B
Rat
Human
116
73.7
21.2
17.6
18.8
9.7
3.3
Figure 2. Covalent binding of radiolabeled 2 to proteins in rat and human liver microsomal (A) and S9 fractions (B) with and without co-factors.

2346
S. K. Nair et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2344–2348
for conjugative enzymes (glucuronyltransferases, sulfotransferases
etc.) (Fig. 2). Further, in vivo covalent binding studies with 14C-la-
beled 2 showed insignificant binding to liver protein [<0.05% of
dose (2 mg/kg), 0.21 pmol/mg]. Both studies indicated that the le-
vel of covalent binding was significantly below the threshold value
of 50 pmol drug equiv/mg proposed as guidance for the industry at
the time of its evaluation.10 Furthermore, in vivo studies in rat did
not show the presence of GSH conjugates in the bile or urine and a
rat in vivo tolerance study (IVT) showed no observed toxicities,
even in a glutathione depleted arm of the study.
MeO
O
HO
O
O
O
S
S
Ar
N
N
CH3
Ar
N
H
N
CH3
H
11
3
O
O
O
GSH
S
GS3
Ar
N
N
CH2
H
5
It has been reported that drugs administered at a daily dose of
10 mg or less have rarely been associated with idiosyncratic drug
toxicities.11 The human dose prediction for 2 was 0.3–3 mg QD
based on PK/PD data, which suggested a lower risk of any possible
adverse effects with this promising 11b-HSD1 inhibitor. Based on
these risk benefit assessments, 2 was evaluated further in healthy
human volunteers in Phase I studies, which also assessed the
safety, tolerability and pharmacokinetics.12
CN
Scheme 2. Proposed bioactivation of 11.
Ar =
the case of 1. Evaluation of 11 in the GSH assay indeed revealed the
same GSH conjugate as that obtained in the bioactivation of 1 (GS3,
see Supplementary data).
Although we were able to alleviate the potential liability of the
observed bioactivation, the inability to predict the outcome of a
positive finding in the GSH assay led us to look at ways to further
minimize or eradicate this risk. The main theme of this strategy
was to make judicious chemical modifications to the sulfonamide
series that would overcome this liability, and use the GSH assay
as a screen for the observed bioactivation. The first step in
approaching this strategy was to rationalize the observed findings
by proposing a mechanistic hypothesis. This hypothesis was cen-
tered on the bioactivation of the electron rich portion of these mol-
ecules, namely the core pyridine ring. Thus, it was proposed that
compound 1 could undergo P450 mediated hydroxylation either
at the 3- or 5-position (3 and/or 4) on the pyridine ring followed
by further oxidation to the reactive quinone methide species (5
and/or 6) which then undergoes a Michael addition with GSH
(Scheme 1). Analogously, amino pyridine 2 could generate the qui-
none imine species (9 and/or 10) as the reactive metabolite and
yield the corresponding sulfhydryl conjugates.
With a mechanistic rationalization in place, we decided to pur-
sue the strategy of chemical modification by applying two key ap-
proaches: (a) blocking the proposed sites of metabolism on the
pyridine ring or creating steric hindrance around these sites, and
(b) evaluating compounds with metabolic ‘soft spots’ that could
provide a divergence from the proposed bioactivation pathway.
The long half-lives and low clearance observed in this series of
compounds added further rationale to evaluate the latter strategy.
From a design perspective, the key consideration in the execution
of both these approaches was the retention of the exquisite po-
tency and an acceptable pharmacokinetic profile.
As part of our efforts to block the proposed sites of metabolism
and/or build steric hindrance to the bioactivation in sulfonamides
1 and 2, the sulfonamides 11–18 (Table 2) were synthesized. The
synthesis of 18 is shown in Scheme 3 as a representative example.
Table 2 captures the results of the reactive metabolite assay
(GSH assay) as well as potency in the cellular assay against human
11b-HSD1 (HEK293, EC50). The addition of a methyl group at the 4-
position, as in compound (12), maintained potency but showed a
positive signal in the GSH assay. In contrast, placing a methyl
group at the 5-position (13) eroded the potency and also showed
a positive finding in the GSH assay. The role of fluorine as a block-
ing group and in the structure–activity relationship was evaluated
In order to verify the proposed metabolic pathway for 1, sulfon-
amide 11 (Scheme 2), with a methoxy substitution at the 3-posi-
tion of the pyridine ring, was synthesized. It was presumed that
the methoxy group in 11 could undergo demethylation and oxida-
tive biotransformation to the identical reactive intermediate 5 as in
HO
O
O
O
O
O
S
S
S
Ar
N
N
N
CH3
Ar
N
N
CH2
H
H
O
O
GSH
GS3
3
or
5
S
Ar
N
N
CH3
or
H
OH
O
1
O
O
O
O
S
Ar
N
H
CH3
Ar
N
N
CH2
H
4
6
HO
O
O
O
O
O
S
S
Ar
N
H
N
N
NH2
Ar
N
N
NH
H
O
O
GSH
7
9
or
S
GS1, GS2
Ar
N
H
N
NH2
or
OH
O
2
O
O
O
O
S
S
Ar
N
NH2
Ar
N
N
NH
H
H
8
10
CN
Ar =
Scheme 1. Proposed bioactivation pathways for 1 and 2.

S. K. Nair et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2344–2348
2347
Table 2
Table 3
Reactive metabolite
assaya
HEK 293 EC50
(nM)
Reactive metabolite
assay
HEK 293 EC50
(nM)
O
O
O
O
S
S
1
2
Positive
Positive
53
5
1
S
S
S
S
S
Positive
Positive
Positive
Negative
53
5
Ar
N
N
N
CH3
NH2
Ar
N
N
N
CH3
NH2
H
H
O
O
O
O
2
Ar
N
H
Ar
N
H
H3CO
O
O
O
O
19
20
10
58
11
12
Positive
Positive
>10
21
lM
S
Ar
N
H
NHEt
OH
N
N
N
N
Ar
N
CH3
H
CH3
O
O
Ar
N
H
O
O
S
S
S
Ar
N
H
N
N
N
CH3
CH3
O
O
21a
22b
23b
24
Negative
ND
327
184
1161
51
Ar
N
H
O
O
OH
OH
OH
OH
OH
13
14
Positive
Positive
213
Ar
N
CH3
O
O
H
S
S
S
S
F
O
Ar
N
H
N
N
N
N
O
1980
Ar
N
H
CH3
F
O
O
ND
Ar
N
H
O
O
15
16
17
Positive
Positive
Negative
194
0.03
72
S
S
Ar
N
H
N
N
CH3
O
O
Negative
Negative
Ar
N
H
O
O
Ar
N
H
O
O
N
25c
26
936
Ar
N
H
O
O
S
S
Ar
N
H
N
O
O
CH3
S
S
Negative
Negative
423
604
Ar
N
H
N
N
OH
O
O
18
Negative
49
O
O
Ar
N
H
N
NH2
CN
27
Ar
N
H
Ar =
CN
Ar =
a
Compounds were incubated in human liver microsomes in presence of NADPH
and reduced glutathione (GSH).
a
b
c
Racemic.
Single enantiomer, absolute stereochemistry not determined.
Absolute stereochemistry determined by Mosher analysis of MTPA ester.
SO2Cl
CH3
N
a mass of 671 Da, similar to that observed of GS3. This result can be
rationalized by a mechanism that involves an oxidative dehalogen-
ation13 and subsequent formation of either of the quinone meth-
ides as the reactive species. The introduction of a fused ring in
the form of the quinoline 16 showed improved potency (EC50
0.03 nM) but was also found to be positive in the GSH assay.
Although no attempt was made to characterize this GSH adduct,
its formation presumably arises from hydroxylation at the 6-posi-
tion of the quinoline and subsequent oxidation to and trapping of a
cross-conjugated reactive quinone imine species.
The placement of a nitrogen atom in the fused ring in naph-
thyridine 17 served as a divergence to the aforementioned path-
way thus yielding an analog that showed no evidence of GSH
adduct formation, albeit with diminished cellular potency (EC50
72 nM). Gratifyingly, the addition of a methyl group at the 4-posi-
tion in the 2,6-diaminopyridine 18 provided an analogue that
showed no formation of a GSH conjugate and reasonable potency
(EC50 49 nM). This outcome is most likely driven by a combination
a
+
H2N
NH2
NC
NC
CH3
N
O
O
b
S
N
NH2
H
18
NC
Scheme 3. Reagents and conditions: (a) (i) ClSO3H, CH2Cl2, 10 °C, (ii) NaOH, (iii)
POCl3, 106 °C, 40%; (b) pyridine, CH2Cl2 (48%).
next. The presence of fluorine at the corresponding 3-(14) and 5-
(15) positions led to diminished potency. However, both these
compounds resulted in a GSH adduct that had a molecular ion with

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S. K. Nair et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2344–2348
O
O
Major
Pathway
S
OH
CO2H
OH
O
O
N
H
N
O
O
O
O
S
S
OH
OH
N
N
N
N
HO
H
H
O
NC
20
28
29
Minor
Pathway
HO
Glucuronide
Conjugates
O
No GSH Adducts
X
O
S
OH
N
N
H
Hydroxylated
Metabolite
Scheme 4. Alternate metabolic pathways observed for 20.
Table 4
Acknowledgment
Rat pharmacokinetic data for 18 and 20
We thank Kai Liu for the Mosher ester analysis and Dr. Jennifer
Lafontaine and Dr. Simon Bailey for careful review of this Letter.
Cl (mL/min/kg)
Vss (L/kg)
T1/2 (h)
F (%)
18
20
0.25
0.11
0.23
0.12
17
12
81
100a
Supplementary data
Dosed at 0.1 mg/kg iv and 0.5 mg/kg p.o.
a
32% When dosed as suspension in 0.5% methylcellulose.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.
02.066.
of steric hindrance and the oxidation of the 4-methyl group as an
alternate metabolic pathway.
References and notes
Building further on the theme of metabolic ‘soft spots’, com-
pounds 19–26 were evaluated in the GSH assay (Table 3). Although
placing alkyl groups on the amino group, exemplified by 19, did
not preclude adduct formation, replacing the amino group with
various substituted alcohols resulted in compounds 20–26 that
were devoid of GSH adducts. Interestingly, compound 27, with
no substitution at the 6-position also provided a negative result,
presumably due to the formation of the N-oxide metabolite. This
outcome also alluded to the role played by the steric environment
in the 2,6-disubstituted pyridines that predicated the ring hydrox-
ylation as the predominant biotransformation pathway.
From an SAR perspective, with the exception of 26, addition of
the alcohol substituents maintained potency, with an enantiomeric
effect observed in the case of secondary alcohols 21–24. The lack of
reactive metabolite formation in case of alcohols such as 20 can be
attributed to competing detoxification pathways that include the
oxidation of the primary alcohol functionality to a carboxylic acid
and its conjugation via glucuronidation. Incubation of alcohol 20
with human liver microsomes and human S9 fractions fortified
with NADPH and UDGPA indeed afforded 28 and 29 as major
metabolites (Scheme 4).
Based on their favorable in vitro profiles and outcomes in the
reactive metabolite assay, 18 and 20 were evaluated in in vivo
rat pharmacokinetic studies and the results are shown in Table 4.
Both of these compounds showed excellent pharmacokinetic pro-
files with half-lives and oral bioavailability similar to 1 and 2.
In summary, assessments of covalent binding and human dose
prediction early in the drug discovery effort enabled the progres-
sion of PF-915275 (2) into a Phase I clinical study. Chemical mod-
ifications made to overcome the reactive metabolite formation in
the N-(pyridin-2-yl) arylsulfonamide series through design and
synthesis have provided promising 11b-HSD1 inhibitors such as
18 and 20 with good cellular potency and in vivo pharmacokinetic
properties.
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