Design, synthesis, and evaluation of (2S,4R)-Ketoconazole sulfonamide analogs as potential treatments for Metabolic Syndrome

Article abstract of DOI:10.1016/j.bmcl.2016.10.016

Metabolic Syndrome, also referred to as ‘Syndrome X’ or ‘Insulin Resistance Syndrome,’ remains a major, unmet medical need despite over 30 years of intense effort. Recent research suggests that there may be a causal link between this condition and abnormal glucocorticoid processing. Specifically, dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis leads to increased systemic cortisol concentrations. Cushing’ syndrome, a disorder that is also typified by a marked elevation in levels of cortisol, produces clinical symptomology that is similar to those observed in MetS, and they can be alleviated by decreasing circulating cortisol concentrations. As a result, it has been suggested that decreasing systemic cortisol concentration might have a positive impact on the progression of MetS. This could be accomplished through inhibition of enzymes in the cortisol synthetic pathway, 11β-hydroxylase (Cyp11B1), 17α‐hydroxylase‐C17,20‐lyase (Cyp17), and 21‐hydroxylase (Cyp21). We have identified a series of novel sulfonamide analogs of (2S,4R)-Ketoconazole that are potent inhibitors of these enzymes. In addition, selected members of this class of compounds have pharmacokinetic properties consistent with orally delivered drugs, making them well suited to further investigation as potential therapies for MetS.

Full text of DOI:10.1016/j.bmcl.2016.10.016

Accepted Manuscript
Design, synthesis, and evaluation of (2S, 4R)-Ketoconazole sulfonamide ana-
logs as potential treatments for metabolic syndrome
Benjamin E Blass, Pravin Iyer, Magid Abou-Gharbia, Wayne W Childers, John
C Gordon, Mercy Ramanjulu, George Morton, Premkumar Arumugam,
Joshodeep Boruwa, John Ellingboe, Sayan Mitra, Rajashekar Reddy
Nimmareddy, Shalini Paliwal, Jamallamudi Rajasekhar, Savithiri Shivakumar,
Pratima Srivastava, Raghuram S. Tangirala, Konda Venkataramanaiah, Mahesh
Yanamandra
PII:
S0960-894X(16)31045-9
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.10.016
BMCL 24319
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 June 2016
3 September 2016
7 October 2016
Please cite this article as: Blass, B.E., Iyer, P., Abou-Gharbia, M., Childers, W.W., Gordon, J.C., Ramanjulu, M.,
Morton, G., Arumugam, P., Boruwa, J., Ellingboe, J., Mitra, S., Nimmareddy, R.R., Paliwal, S., Rajasekhar, J.,
Shivakumar, S., Srivastava, P., Tangirala, R.S., Venkataramanaiah, K., Yanamandra, M., Design, synthesis, and
evaluation of (2S, 4R)-Ketoconazole sulfonamide analogs as potential treatments for metabolic syndrome,
Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.10.016
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Design, synthesis, and evaluation of (2S, 4R)-
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Benjamin E Blass, Pravin Iyer, Magid Abou-Gharbia, Wayne W Childers, John C Gordon, Mercy Ramanjulu,
George Morton, Premkumar Arumugam, Joshodeep Boruwa, John Ellingboe, Sayan Mitra, Rajashekar Reddy
Nimmareddy, Shalini Paliwal, Jamallamudi Rajasekhar, Savithiri Shivakumar, Pratima Srivastava, Raghuram S.
Tangirala, Konda Venkataramanaiah, and Mahesh Yanamandra.

Bioorganic & Medicinal Chemistry Letters
Design, synthesis, and evaluation of (2S, 4R)-Ketoconazole sulfonamide analogs
as potential treatments for metabolic syndrome
b
Benjamin E Blassa ,  Pravin Iyer , Magid Abou-Gharbiaa, Wayne W Childersa, John C Gordona, Mercy
Ramanjulua, George Mortona, Premkumar Arumugamb, Joshodeep Boruwab, John Ellingboeb, Sayan
Mitrab, Rajashekar Reddy Nimmareddyb, Shalini Paliwalb, Jamallamudi Rajasekharb, Savithiri
Shivakumarb, Pratima Srivastavab, Raghuram S. Tangiralab, Konda Venkataramanaiahb, and Mahesh
Yanamandrab
aMoulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N Broad Street, Philadelphia, PA 19140 USA.
bGVK Biosciences Private Limited, Plot 28A, IDA Nacharam, Hyderabad, India 500076.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Metabolic syndrome, also referred to as “Syndrome X” or “Insulin Resistance Syndrome,”
remains a major, unmet medical need despite over 30 years of intense effort. Recent research
suggests that there may be a causal link between this condition and abnormal glucocorticoid
processing. Specifically, dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis
leads to increased systemic cortisol concentrations. Cushing’ syndrome, a disorder that is also
typified by a marked elevation in levels of cortisol, produces clinical symptomology that is
similar to those observed in MetS, and they can be alleviated by decreasing circulating cortisol
concentrations. As a result, it has been suggested that decreasing systemic cortisol concentration
might have a positive impact on the progression of MetS. This could be accomplished through
inhibition of enzymes in the cortisol synthetic pathway, 11β-hydroxylase (Cyp11B1),
17α‐hydroxylase‐C17,20‐lyase (Cyp17), and 21‐hydroxylase (Cyp21). We have identified a
series of novel sulfonamide analogs of (2S, 4R)-Ketoconazole that are potent inhibitors of these
enzymes. In addition, selected members of this class of compounds have pharmacokinetic
properties consistent with orally delivered drugs, making them well suited to further
investigation as potential therapies for MetS.
Keywords:
Metabolic syndrome
Ketoconazole
Cortisol
17α‐hydroxylase‐C17,20‐lyase (Cyp17)
2009 Elsevier Ltd. All rights reserved.
———
 Corresponding author. Tel.: +1-215-707-2218; fax: +1-215-707-5296; e-mail: Benjamin.Blass@Temple.edu

Over the course of the last three decades, a growing body of
knowledge has been developed to describe Meta-bolic Syndrome
(MetS), also referred to as “Syndrome X” or “Insulin Resistance
Syndrome.”1 MetS is defined as a cluster of abnormalities that
occur in concert, including high blood pressure (BP),
hyperglycemia, reduced high density lipoprotein cholesterol
(HDL-C) levels, elevated triglycerides (TG) and abdominal
obesity. The most widely accepted definition of this condition is
based on the National Cholesterol Education Program (NCEP)
Adult Treatment Panel-III (ATP-III), which provides for the
diagnosis of MetS in patients that meet at least three of the
following parameters identified in Table 1. Current estimates
indicate that nearly 25% of the world’s adult population suffers
from MetS, and the incidence is rising, largely as a result of
increased obesity rates.2
17 (hydroxylase activity), while the C-20/C-17 bond is cleaved
by the same enzyme in 17α-hydroxyprogesterone and 17-
hydroxypregnenolone (lyase activity). Finally, Cyp21 catalyzes
the hydroxylation of C-21 in steroids such as progesterone and
17α-hydroxyprogesterone.
Although there has been some
progress in the identifying selective Cyp11B1 inhibitors,7 none
has reached the market. In addition, accumulation of cortisol
precursors represents an added risk to Cyp11B1 inhibition. This
risk could be avoided by targeting Cyp17 and/or Cyp21, each of
which is important to cortisol synthesis.8
Table 1: Metabolic Syndrome diagnostic parameters
Parameter
Waist size
HDL-C
TG
BP
Men
Women
>88 cm
<50 mg/dL
>150 mg/dL
>130/85
>102 cm
<40 mg/dL
>150 mg/dL
>130/85
Figure 1: Marketed azole antifungal agents (1) ()-Ketoconazole,
(2) Itraconazol, (3) Fluconazole
Efforts to develop novel therapies for the treatment of MetS
recently led to the identification of (±)-Ketoconazole (1) as an
agent capable of lowering plasma cortisol concentrations. (±)-
Ketoconazole was originally identified in 1979 by scientists at
Janssen Pharmaceuticals as a potent antifungal agent.9 It was the
first orally active azole antifungal agent. Although itraconazole10
(2) and fluconazole11 (3) have proven to be safer and more
effective for systemic fungal infections, (±)-Ketoconazole
remains a major therapeutic tool for the treatment of fungal
infections of the skin such as athlete’s foot, ringworm, and
candidiasis. The antifungal activity of (±)-Ketoconazole is
driven by its ability to inhibit the synthesis of ergosterol, an
important component of fungal cell membranes, by inhibiting
Cyp450--demethylase.12 (±)-Ketoconazole is also known as a
potent inhibitor of Cyp3A4. As a result oral dosage forms are
associated with a warning for potential drug-drug interaction with
a wide range of important medications such as Imatinib,
Simvastatin, Alprazolam, and Indinavir.13
Fasting Glucose
>110 mg/dL
>110 mg/dL
While there are many factors that contribute to the
development of MetS, there is strong support for the theory that
abnormal glucocorticoid processing plays an important role in the
progression of this condition.
The glucocorticoids were
originally named for their contribution to glucose metabolism,
but it has since been shown that they play a much wider role in
resting and stress related homeostasis. Cortisol in particular has
been implicated in MetS by virtue of the high degree of similarity
between the clinical manifestation of MetS and Cushing’s
syndrome.
Much like MetS, the clinical manifestations of
Cushing’s syndrome include central obesity, hypertension,
dyslipidemia, and insulin resistance that may manifest as
impaired glucose tolerance or type 2 Diabetes.3 Cushing’s
syndrome is also typified by a marked elevation in levels of
cortisol. Surgical intervention at the pituitary or adrenal level
leads to a marked decrease in centralization of fat deposits
observed in patients with Cushing’s syndrome. This result can
be attributed to decreased levels of circulating cortisol as a result
of the surgical intervention. In related findings, it has been
demonstrated that exogenous treatment with glucocorticoids
leads to the development of abdominal obesity in both animals
and humans, further suggesting that glucocorticoids play an
important role in the development of this phenotype. Also,
animal models of obesity are known to demonstrate elevated
levels of corticosterone (the equivalent of cortisol in humans).4
Table 2: Ketoconazole Cyp17 and Cyp3A4 data
Cyp17* Cyp3A4*
IC50 (nM)
Ratio
Compound
(±)-Ketoconazole
(2S, 4R)-Ketoconazole
(2R, 4S)-Ketoconazole
93
48
133
146
136
1.4
3.0
1800
0.076
* n = 3
Recently, it has been demonstrated that (±)-Ketoconazole is a
potent inhibitor of Cyp17,14 which, as noted above, is a key
player in cortisol synthesis. In an effort to gain a better
understanding of the relationship between cortisol synthesis and
MetS, Per Marin et. al. examined the impact of 400 mg daily oral
doses of (±)-Ketoconzaole in group of 30 female MetS patients.
After 3 months, statistically significant improvements in multiple
risk factors associated with MetS (insulin resistance, total
cholesterol, fasting glucose levels, HbA1C levels, and blood
pressure) were observed. These findings strongly support the
application of cortisol synthesis inhibitors for the treatment of
MetS, as well as the importance of Cyp17 as a therapeutic target
for this condition.15 The potential utility of (±)-Ketoconazole for
the treatment of MetS is, however, limited by its potent inhibition
of Cyp3A4. The MetS patient population is likely to be using
multiple medications, raising the likelihood of adverse drug/drug
interactions if (±)-Ketoconazole were to be added to the mix.
Taken together, these findings strongly suggest that
modulation of glucocorticoid processing may be a viable
approach to the treatment of MetS and related disorders. One
possible method of correcting the dysregulation of the
hypothalamic-pituitary-adrenocortical (HPA) axis associated
with MetS is decreasing circulating cortisol level. This could be
accomplished by inhibiting one or more of the enzymes in the
cortisol synthetic pathway.
hydroxylase (Cyp11B1),
Viable targets include 11β-
17α-hydroxylase-C17,20-lyase
(Cyp17),5 and 21-hydroxylase (Cyp21).6 All three are members
of the cytochrome P450 superfamily of enzymes. Cyp11B1
catalyzes the final step of cortisol synthesis, hydroxylation of the
C-11 position of deoxycortisol. Cyp17 has multiple functions in
corticosteroid synthesis. The C-17 and C-20 positions of the
steroid framework can be modified by this enzyme.
Pregnenolone and progesterone are hydroxylated by Cyp17 at C-

racemic deacylated (±)-Ketoconazole from the parent racemate.18
Thus, deacylation of the enantiomerically pure (2S, 4R)-
Ketoconazole provided us with easy access to a functionalizable
piperazine nitrogen within the (2S, 4R)-Ketoconazole framework
(5). Functionalization with a suitable sulfonyl chloride in the
presence of trimethylamine provided rapid access to numerous
analogs suitable for in vitro screening (Scheme 1).
Interestingly, the individual enantiomers of (±)-Ketoconazole
are not equally potent inhibitors of Cyp17.16 Although the (2s,
4R) isomer potently inhibits Cyp17 (IC50 = 48 nM), its mirror
image, the (2R, 4S) isomer, is much less potent (IC50 = 1800
nM). The same is not true, however, of their activity at Cyp3A4,
as the two enantiomers are nearly equipotent at this key
metabolic enzyme (Table 2). The difference in Cyp17 activity
provides the (2s, 4R) isomer with
a
slightly better
As indicated in Table 3, replacing the acetyl group of (2S,
4R)-Ketoconazole (4) with a sulfonamide provides compounds
with substantial inhibitory potency at Cyp17 (IC50 67 – 0.73 nM).
Potency at Cyp3A4 was also maintained, but to a lesser extent
(IC50 99 – 450 nM). In addition, differences in the SAR patterns
of Cyp17 and Cyp3A4 enabled the identification of compounds
with a higher degree of selectivity as compared to the parent
compound (4). Installation of a methyl sulfonamide (6a), for
example, produced a 3 fold increase in Cyp17 potency, while
Cyp3A4 activity remained nearly unchanged. These differences
produce a net effect of increasing Cyp17 selectivity from 3 fold
to >10 fold. Extending the sulfonamide by one additional carbon
atom (6b) lead to an additional >20 fold increase in Cyp17
potency (0.73 nM) and once again Cyp3A4 activity remained
nearly unchanged (162 nM), leading to a 222 fold selectivity
factor. The more sterically encumbered isopropyl sulfonamide
(6c) was less potent at Cyp17 (12 nM) than 6b and therefore less
selective versus Cyp3A4 (16.5 fold). Reducing the steric
footprint of the isopropyl sulfonamide by incorporating the
corresponding cyclopropyl ring restores some of the Cyp17
activity (3.7 nM) and Cyp3A4 selectivity (50 fold). Further
elongation of the sulfonamide, as seen in the methoxyethyl
analog (6e), led to an increase of Cyp17 potency (19 nM).
Cyp3A4 potency, however, was little changed, and as a result
the corresponding improvement of Cyp17/3A4 selectivity was
moderate (9.7 fold). Restricting the flexibility of the methyl
ether of 6e via closure of a six membered ring led to an increase
in Cyp17/3A4 selectivity (20.5 fold), as Cyp17 potency increased
(11 nM) while Cyp3A4 potency decreased (226 nM).
Cyp17/Cyp3A4 ratio, which may translate into a lower risk of
drug/drug interactions in a clinical setting. In fact, this
compound is currently the subject of on-going phase clinical
studies for the treatment of endogenous Cushing’s syndrome.17
A
positive result would provide patients in need with a new
therapeutic option. Reducing the inhibition of CYP3A4 and
thereby the risk of drug/drug interactions could be a further
improve of this class of drugs.
Scheme 1: Synthesis of (2S, 4R)-Ketoconazole analogs 6a-6l
(a) NaOH, MeOH/H2O (1/1), reflux 18 h. (b) RSO2Cl, NEt3, CH2Cl2,
25 oC, 18 h.
In an effort to address the Cyp3A4 issue, we launched a
program designed to identify novel Cyp17 inhibitors with
increased Cyp3A4 selectivity. As a first step on this road, we
chose to focus on direct analogs of (2S, 4R)-Ketoconazole. To
our surprise, there have been very few literature reports of (±)-
ketoconazole analogs since its initial disclosure, and none
focused on their potential as Cyp3A4 inhibitors. There were,
however, a limited number of disclosures of the preparation of
Table 3: Physicochemical and in vitro screening results of exemplary (2S, 4R)-Ketoconazole analogs.
Cyp17* Cyp11* Cyp21* Cyp19* Cyp3A4*
GPLM**
t1/2 (min)
Entry
R
MW cLogP TPSA
Cyp3A4/Cyp17
IC50 (nM)
NA
Me
531
567
581
595
593
5.2
4.1
4.5
4.9
4.6
3.9
69
86
86
86
86
95
48
15
116
500
63
4300
1600
970
146
158
162
198
185
185
3.0
10.5
222
16.5
50
45
25
25
33
19
56
4
1600
271
51
6a
6b
6c
6d
6e
Et
0.73
12
1600
1200
1820
10000
i-Pr
40
cyc-Pr
3.7
19
58
28
CH2CH2OMe 611
637
110
166
9.7
4.5
95
11
187
123
1240
226
20.5
15
6f
CF3
CHF2
621
603
592
645
5.4
4.8
3.6
3.4
86
86
67
8
32
29
70
67
49
26
78
20
790
336
99
5.0
22
30
51
25
6g
6h
6i
3800
2800
1000
12.4
17.0
21.6
CH2CN
CH2SO2Me
110
120
9
153
151
7
6j
635
633
6.1
5.3
86
9
82
17
148
8
10000
10000
87
9.7
9.7
21
18
6k
6l
104
15
145
* n = 3, **GPLM = guinea pig liver microsome

Incorporation of electron withdrawing substituents into the
sulfonamide group also produced interesting results. Selectivity
for Cyp17 versus Cyp3A4 was slightly improved (5 fold
selectivity) by replacing the methyl of 6a with a trifluormethyl
group (6g) as a result of a moderate increase in Cyp17 potency
(67 nM) and a moderate decrease in Cyp3A4 potency (336 nM).
Greater improvement in selectivity was observed with the
potent at Cyp19 than the original lead compound (4). In some
cases (6e, 6k, and 6l), Cyp19 is completely eliminated. Only two
compounds, the methyl sulfonamide analog (6a) and the
trifluoromethyl sulfonamide analog (6g), had Cyp19 IC50s below
1000 nM.
Having identified a series of interesting inhibitors of enzymes
critical to cortisol synthesis, we next turned our attention to an
evaluation of their pharmacokinetic properties. Given the
chronic nature of MetS, we felt that oral delivery would be
critical to successful therapeutic intervention. In an effort to
identify compounds capable of oral delivery, we first determined
the metabolic half-life (t1/2) of our compounds in guinea pig liver
microsomes (GPLM, table 3). The guinea pig is an established
model of metabolic syndrome and methods for cortisol
measurement in this species have been previously reported.20 As
indicated in table 3, GPLM stability was moderate (6f, t1/2 = 15
min) to high (6e, t1/2 = 56 min), which suggested that this series
of compounds may have sufficient metabolic stability for
therapeutic application. In addition, calculated properties (cLogP
and TPSA) are suggestive of good permeability, with the notable
exception of 6k, whose cLogP of 6.1 is outside of the desired
range (typically 1-5).21 It is worth noting, however, that even
though (±)-Ketoconazole’s cLogP is also slightly higher than the
desired range (cLogP = 5.2), it is a successful, orally active
therapeutic. This suggests that there may be some degree of
latitude in the acceptable cLogP values within this class of
compounds.
difluoromethyl
(6h),
cyanomethyl
(6i),
and
methylsulfonylmethyl (6j) analogs. In each of these three
examples, Cyp17 potency increased by a factor of 5, while
Cyp3A4 potency remained comparable to that observed with (2S,
4R)-Ketoconazole (4). Similar effects are observed with the
incorporation of a 2-thiophene (6k) and N-methyl-2-imidazole
(6l).
The impact of the sulfonamide analogs on three other enzymes
that are critical to the synthesis of glucocorticoid processing,
Cyp11B1, Cyp21, and Cyp19, was also explored. As indicated in
table 3, (2S, 4R)-Ketoconazole (4) is a nearly as potent an
inhibitor of Cyp11B1 as Cyp17 (116 nM vs. 48 nM). The
majority of the corresponding sulfonamide derivatives examined
were also potent Cyp11B1 inhibitors. While the installation of a
methyl sulfonamide (6a) produces a >4-fold decrease in Cyp11
potency (500 nM), elongation of the sulfonamide (6b-6d) led to
an increase of Cyp11 inhibition relative to that of (2S, 4R)-
Ketoconazole (4). The larger methoxyethyl (6e) analog and the
4-tetrahydropyranyl analog (6f), on the other hand, are nearly
equipotent with the initial lead compound (4). Electron
withdrawing groups (6g-6j), 2-thiophene (6k), and N-methyl-2-
imidazole (6l) substitution on the sulfonamide also led to
increased Cyp11 potency. Interestingly, 6l is nearly equipotent at
Cy11B1 and Cyp17 (17 nM versus 15 nM).
Next, a small set of compounds (6b, 6c, 6d, and 6i) was
selected for in vivo pharmacokinetic evaluation in guinea pigs.
Age matched, male Hartley guinea pigs were given a single dose
of a test compound via both IV (1 mg/kg) and PO (10 mg/kg) and
plasma samples were acquired in order to measure standard PK
parameters. As indicated in table 4, small structural changes in
the sulfonamide had a significant impact on guinea pig
pharmacokinetic properties. The ethyl sulfonamide (6b), for
example, is moderately bioavailable (61.4%) and has an oral in
vivo half-life of 3.1 hours, but the addition of a single methyl
group (the isopropyl sulfonamide, 6c) leads to a substantial loss
in oral bioavailability (10.4%) and decreased oral in vivo half-life
(t1/2 = 2.2 h). In contrast, the corresponding cyclopropyl
sulfonamide (6d) is highly bioavailable (98.5%) and its PO half-
life (t1/2 = 2.9 h) is similar to that observed for 6b. This result
was unexpected, as in vitro GPLM data (table 3) had suggested
that 6b would be more metabolically stable than 6c. Similarly,
installation of the electron withdrawing cyano group (6i) led to a
decrease in oral half-life (2.5 h) and oral bioavailability (39.5%),
despite its high stability in GPLM. This suggests that factors
other than phase 1 metabolism (e.g. protein binding, phase 2
Table 4: Guinea pig in vivo pharmacokinetic profiles of
exemplary (2S, 4R)-Ketoconazole analogs.
(n = 3)
6b
6c
6d
6i
Dose(mg/kg)
Delivery*
1
10
1
10
1
10
1
10
PO
IV PO IV PO IV PO IV
Cmax(ng/mL) 446 710 534 358 514 1556 2091 1967
Tmax (h)
t1/2 (h)
0.1 1.17 0.19 0.67 0.08 1.5 0.08 0.67
1.7 3.1 1.1 2.2 1.4 2.9 2.0 2.5
Vd (L/kg)
Cl
(mL/min/kg)
AUC0-inf
(ng·h/mL)
%F
4.4
3.0
2.9
2.5
30.5
31
23.8
14.3
560 3714 547 571 715 7576 1165 4599
61.4 10.4 98.5 39.5
*IV vehicle: 20%DMA, 40%TEG, 40%Water. PO vehicle: 98%
HPMC (1% in water), 2% Tween80.
Interestingly, Cyp21 potency was significantly increased
relative to (2S, 4R)-Ketoconazole (4) in all of the sulfonamides
examined. While the methyl sulfonamide analog (6a) increased
Cyp21 activity by a factor of just over 2.6x, larger substituents
produced more dramatic results. The addition of a single
additional carbon (6b), for example, led to an increase in Cyp21
potency of >15 fold (271 nM). This compound is also notable, as
its Cyp17/Cyp21 selectivity is the highest observed in the series
(>370x) as a result of its high potency at Cyp17 (0.73 nM). The
most potent Cyp21 inhibitor identified to date in this series, 6l
(8.0 nM), is also noteworthy. Not only is it >530 fold more
potent at Cyp21, it is also nearly equipotent at Cyp17 and
Cyp11B1, and it is inactive at Cyp19 (10,000 nM). Selectivity
with respect to Cyp19 is an important aspect of potential
therapeutic agents, as compounds that are potent inhibitors of
Cyp19 (also known as Aromatase) may interfere with estrogen
synthesis.19 The majority of compounds examined were less
metabolism) may be playing
pharmacokinetic profile of this class of compounds.
a significant role in the
In summary, we have identified a novel series of sulfonamide
analogs of (2S, 4R)-Ketoconazole that are capable of inhibiting
key enzymes in the cortisol synthetic pathway. Exemplary
compounds examined in this series possess in vivo
pharmacokinetic properties necessary for in vivo efficacy studies
in guinea pig models of MetS to determine their potential for
therapeutic utility. The results of these studies are pending.
ACKNOWLEDGMENT
We would like to thank the dean of Temple University School
of Pharmacy, Peter
H Doukas, for his support and
encouragement in pursuing this program. We would also like
to the administrative staff of Temple University School of
Pharmacy for their assistance. Funding for this program was

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19. Simpson, E. R.; Clyne, C.; Rubin, G.; Boon, W. C.; Robertson, K.;
Britt, K.; Speed, C.; Jones, M. Aromatase--a brief overview.
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provided by Strongbridge Biopharma plc, 900 Northbrook
Drive, Suite 200, Trevose, PA 19053 United States. Prior to
September 4th, 2015, Strongbridge Biopharma plc was known as
Coretendo plc.
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