Design and synthesis of functionalized piperazin-1yl-(E)-stilbenes as inhibitors of 17α-hydroxylase-C17,20-lyase (Cyp17)

Article abstract of DOI:10.1016/j.bmcl.2018.05.040

The synthesis of steroid hormones is critical to human physiology and improper regulation of either the synthesis of these key molecules or activation of the associated receptors can lead to disease states. This has led to intense interest in developing c

Full text of DOI:10.1016/j.bmcl.2018.05.040

Accepted Manuscript
Design and synthesis of functionalized piperazin-1yl-(E)-stilbenes as inhibitors
of 17α-hydroxylase-C17,20-lyase (Cyp17)
Benjamin E Blass, Pravin Iyer, Magid Abou-Gharbia, Wayne E 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,
Ramreddy Bobbala, Mahesh Yanamandra, L. Krishnakanth Reddy
PII:
S0960-894X(18)30441-4
https://doi.org/10.1016/j.bmcl.2018.05.040
BMCL 25857
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
30 January 2018
17 May 2018
18 May 2018
Please cite this article as: Blass, B.E., Iyer, P., Abou-Gharbia, M., Childers, W.E., 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., Bobbala, R., Yanamandra, M., Reddy, L.K.,
Design and synthesis of functionalized piperazin-1yl-(E)-stilbenes as inhibitors of 17α-hydroxylase-C17,20-lyase
(
Cyp17), Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.05.040
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Design and synthesis of functionalized
piperazin-1yl-(E)-stilbenes as inhibitors of
Leave this area blank for abstract info.
17α-hydroxylase-C17,20-lyase (Cyp17)
Benjamin E Blass, Pravin Iyer, Magid Abou-Gharbia, Wayne E 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, Ramreddy Bobbala, Mahesh Yanamandra, and L. Krishnakanth Reddy.

ACCEPTED MANUSCRIPT
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Design and synthesis of functionalized piperazin-1yl-(E)-stilbenes as inhibitors of
1
7α-hydroxylase-C17,20-lyase (Cyp17)
a,
b
a
a
a
,
Benjamin E Blass *, Pravin Iyer Magid Abou-Gharbia , Wayne E Childers , John C Gordon , Mercy
a
Ramanjulu , George Morton , Premkumar Arumugam , Joshodeep Boruwa , John Ellingboe , Sayan
a
b
b
b
b
b
b
b
Mitra , Rajashekar Reddy Nimmareddy , Shalini Paliwal , Jamallamudi Rajasekhar , Savithiri
b
Shivakumar , Pratima Srivastava , Raghuram S. Tangirala , Konda Venkataramanaiah , Ramreddy
b
b
b
b
Bobbala, Mahesh Yanamandra and L. Krishnakanth Reddy.
b
b
a
Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N Broad Street, Philadelphia, PA 19140 USA.
GVK Biosciences Private Limited, Plot 28A, IDA Nacharam, Hyderabad, India 500076.
b
ARTICLE INFO
ABSTRACT
Article history:
Received
The synthesis of steroid hormones is critical to human physiology and improper regulation of
either the synthesis of these key molecules or activation of the associated receptors can lead to
disease states. This has led to intense interest in developing compounds capable of modulating
the synthesis of steroid hormones. Compounds capable of inhibiting Cyp19 (Aromatase), a key
enzyme in the synthesis of estrogens, have been successfully employed as breast cancer
therapies, while inhibitors of Cyp17 (17α-hydroxylase-17,20-lyase), a key enzyme in the
synthesis of glucocorticoids, mineralocorticoids and steroidal sex hormones, are a key
component of prostate cancer therapy. Inhibition of CYP17 has also been suggested as a
possible target for the treatment of Cushing Syndrome and Metabolic Syndrome. We have
identified two novel series of stilbene based CYP17 inhibitors and demonstrated that exemplary
compounds in these series have pharmacokinetic properties consistent with orally delivered
drugs. These findings suggest that compounds in these classes may be useful for the treatment
of diseases and conditions associated with improper regulation of glucocorticoids synthesis and
glucocorticoids receptor activation.
Revised
Accepted
Available online
Keywords:
Metabolic syndrome
Ketoconazole
Cortisol
1
7αǦhydroxylaseǦC17,20Ǧlyase (Cyp17)
2
009 Elsevier Ltd. All rights reserved.
Steroid hormones play critical roles in human physiology.
They are primarily synthesized from cholesterol and can be
divided into classes, progestogens, glucocorticoids,
5
mineralocorticoids, androgens, and estrogens. Progestogens such
as progesterone are required for preparing the uterus for and
maintaining pregnancy, while glucocorticoids (e.g. cortisol)
stimulate gluconeogenesis, inhibit inflammation, and increase fat
and protein catabolism.
Androgens (e.g. testosterone) and
estrogens (e.g. estradiol) are well known for their role in the
development of male and female secondary sex traits. Finally,
the mineralonocorticoids (e.g. aldosterone) participate in the
regulation of blood volume and pressure via changes in the
reabsorption of Na and the excretion of K and H in the distal
tubules of the kidneys.
Figure 1: FDA approved CYP17 inhibitors
dyslipidemia, and insulin resistance that may manifest as
+
+
+
2
impaired glucose tolerance or type 2 Diabetes. Prostate cancer
and breast cancer progression have also been linked to aberrant
3
steroid hormone activation of the corresponding receptor. Novel
Each of the aforementioned classes of steroid hormones exerts
its pharmacological effect through a corresponding receptor (e.g.
therapies targeting steroid hormone biosynthesis have been
effectively employed to slow the progression of breast cancer and
1
glucocorticoid receptors, estrogen receptors).
Improper
®
prostate cancer. Specifically, Letrozole (Femara , 1) and
regulation of either steroid hormone concentration or receptor
activation can have serious, possibly fatal results. Over-
production of cortisol, for example, leads to Cushing syndrome, a
disease characterized by central obesity, hypertension,
®
Exemestane (Aromasin , 2) are approved for the treatment of
breast cancer based on their ability to inhibit Cyp19 (Aromatase),
a key enzyme in the synthesis of estradiol. In a similar manner,
compounds that inhibit Cyp17 (17α-hydroxylase-17,20-lyase)

ACCEPTED MANUSCRIPT
Figure 2: Energy minimized structures COR-003, (7), and overlap.
bromostyrene with either 3a or 3b provided intermediate s 5a and
b. Heck coupling with 2a and 2b with 5a provided the
5
corresponding acylated stilbene analogs 6a and 6b, while Heck
coupling of 2a and 2b with 5b provided the corresponding Boc
stilbene analogs 7a and 7b. Removal of the Boc group with HCl,
followed by condensation of the piperazine with a sulfonyl
chloride provided the sulfonamide stilbene analogs (8a-k).
Alternatively, removal of the Boc group with HCl, followed by
condensation of the piperazine with either 1-chloro-2-
isocyanatoethane or 1-chloro-3-isocyanatoethane followed by
triethyl amine provided the corresponding dihydrooxazole (8l,
8
m) and dihydro-4H-1,3-oxazine (8n) respectively. Finally,
condensation of the aforementioned piperazine with 1H-
pyrazole-1-carboximidamide hydrochloride in the presence of
provided the guandinyl analogs 8o and 8p.
st
Table 1: Calculated properties and CYP17 inhibition of 1
11
generation stilbene analogs (6a, 8a to 8o)
1
3
CYP17 IC50
(
Entry
R
R
MW TPSA* cLogP
nM)**
48
42
COR-003 NA
NA
Ac
531
421
457
471
483
69
41
67
67
67
5.2
6a
8a
8b
8c
Cl
Cl
Cl
5.57
4.42
4.84
4.99
MeSO
EtSO
2
180
24
2
Cl cyc-PrSO
2
21
can slow the progression of prostate cancer. The acetate prodrug
®
of Abiraterone (3), Zytiga , was approved by the FDA for this
8d
Cl
509
520
96
80
5.08
4.73
6.2
17
4
5
6
purpose in 2011. Seviteronel (4) and CFG-920 (5) were
identified as Cyp17 inhibitors and are currently undergoing
clinical evaluation as novel therapies for the treatment of prostate
cancer
8
e
Cl
8
f
F
F
F
F
F
MeSO
iPrSO
CF HSO
cyc-PrSO
CNCH SO
2
441
469
477
467
466
67
67
67
67
91
3.91
4.82
4.61
4.48
3.44
58
39
5
The (2S, 4R) isomer of the antifungal agent Ketoconazole,
COR-003 (6), is also a potent Cyp17 inhibitor (48 nM), but its
therapeutic utility in prostate cancer has not been explored. It is,
however, currently undergoing clinical evaluation for the
treatment of Cushing syndrome (Fig. 1). The clinical
manifestations of this condition include central obesity,
hypertension, dyslipidemia, and insulin resistance that may
8
8
g
h
2
2
2
8
8
i
j
2
34
86
2
2
8k
Cl
F
448
432
445
421
404
46
46
46
74
74
4.98
4.47
4.92
4.65
4.13
100
117
42
3
manifest as impaired glucose tolerance or type 2 Diabetes.
Cushing syndrome is also associated with elevated cortisol
7
levels, a glucocorticoid whose biosynthesis is at least in part
8l
8m
F
regulated by CYP17. Notably, the clinical manifestations of
Cushing syndrome are strikingly similar to those of Metabolic
Syndrome (MetS), 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. As a result of
these similarities, it has been hypothesized that CYP17 inhibition
8n
Cl
F
2500
1200
8o
*
TPSA = topological polar surface area, **n = 3
As indicated in Table 1, our stilbene replacement core is
8
may be a viable therapeutic option for the treatment of MetS.
As part of our on-going effort to identify novel Cyp17
inhibitors, we recently reported the preparation and biological
capable of providing compounds with Cyp17 inhibitory potency
comparable to that observed with the ketoconazole analog COR-
0
03 (6). Specifically, the direct analog (6a) had an IC50 of 42 nM
9
properties of a series of sulfonamide analogs of (6) (Fig. 2).
while the original lead compound (6) demonstrated an IC50 of 48
nM. We previously reported that the acetamide of (6) could be
replaced with the corresponding sulfonamide. This strategy was
also effective in the stilbene series. Simple alkyl sulfonamides
While we were able to identify highly potent compounds (IC50’s
as low as 0.73 nM), our ability to prepare additional analogs in
this series was limited by our dependence on a natural product
core. In an effort to overcome this limitation, we considered the
possibility of replacing the ketoconazole scaffold with a stilbene-
derived core. A comparison of the energy minimized structure of
COR-003 (6) and the corresponding stilbene analog (7) suggested
that key binding components of the proposed novel scaffold
(8a, 8b, and 8c) all potently inhibited Cyp17 activity (180, 24,
Figure 3: Energy minimized structures COR-003, (9), and overlap
10
would be similarly positioned (Fig. 2) and a review of the
literature indicated that this class of compounds had not been
reported. We prepared an initial set of screening samples using
the methods described in Scheme 1. Thus, AIBN-mediated
bromination of 1a and 1b with NBS, followed by nucleophilic
displacement of the resulting benzyl bromide with imidazole
provided 2a and 2b. Separately, Buchwald coupling of 4-

ACCEPTED MANUSCRIPT
and 21 nM, respectively). Heteroaromatic groups such as
imidazole (8d, 6.2 nM) and 3-pyridyl (8e, 17 nM) were also well
tolerated, but the corresponding guanidine derivative (8n)
and stilbene (9) suggested that key binding regions of the
12
proposed pyridine analog would be similarly positioned (Fig. 3)
and a review of the literature once again indicated that this class
of compounds had not been reported. Exemplary compounds in
this class were prepared using the methods described in Scheme
2. Initial Suzuki coupling of (10a) or (10b) with 4-(4,4,5,5-
demonstrated a significant decrease in Cyp17 potency (IC50 =
500 nM). The corresponding dihydrooxazole (8k), on the other
2
hand, retained significant activity at the target (IC50 = 100 nM).
tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
provided
the
requisite biaryl species (11a or 11b). Heck coupling with (5a)
under standard conditions provided the acylated derivative (12a)
and (12b), while Heck coupling with (5b) provided the Boc
protected analogs (13a) and (13b). Removal of the Boc group of
(13a) and (13b) under acidic conditions provided the
corresponding free piperazines which were readily condensed
with sulfonyl chlorides to provide the sulfonamide analogs.
Alternatively, removal of the Boc group with HCl, followed by
condensation of the piperazine with 1-chloro-2-isocyanatoethane
followed by triethyl amine provided the corresponding
dihydrooxazole. Finally, condensation of the aforementioned
piperazine with 1H-pyrazole-1-carboximidamide hydrochloride
in the presence of provided the guandinyl analogs.
These findings suggest the presence of a pocket in this region of
the molecule capable of accepting sterically demanding, non-
polar substituents.
As shown in Table 2, our second stilbene core also displayed
significant inhibitory potency against Cyp17. Specifically, the
chlorinated acyl derivative (12a) and the fluorinated acyl
derivative (12b) were ~8 to 9 times as potent our first generation
stilbene derivative (6a) and COR-003 (6). The increased potency
in our second generation stilbene analogs was even more
1
Replacement of the chlorine atom in the R position with a
fluorine atom (e.g., 8f, 8g, 8j, 8i and 8h) provided similarly
potent analogs. A comparison of the calculated properties of the
fluorine analogs, however, revealed that their cLogP is
consistently ~0.5 units lower than the corresponding chlorine
analog. This feature provides additional latitude with respect to
the choice of substituents in other regions of the molecule that
will maintain a cLogP in the drug-like range and could have a
beneficial impact on oral bioavailability of potential lead
candidates.
pronounced when the acyl group was replaced with
a
sulfonamide. Incorporation of a methanesulfonamide into our
chlorinated second generation series (14a), for example,
produced a 36 fold increase in activity when compared to our
first generation series (5 nM vs 180 nM).
This trend of
increased potency in our second generation when compared to
our first generation series was sustained across all of the
sulfonamides that we examined, as well as the dihydrooxazole
bioisosteric analogs. The second generation dihydrooxazoles
nd
Table 2: Calculated properties and CYP17 inhibition of 2
10
generation stilbene analogs (12a, 12b, 14a-14o)
(14n) and (14o) were found to be ~20 fold more potent than the
corresponding first generation compounds (8k and 8l).
CYP17
IC50
1
R
2
R
Entry
MW TPSA* cLogP
(
nM)**
Figure 4: Energy minimized structures (8n), 14l, and overlap.
COR-003 NA
NA
Ac
531
418
454
482
480
479
490
401
438
452
466
464
492
474
69
36
62
62
62
86
62
36
62
62
62
62
62
62
5.20
5.35
4.20
5.12
4.77
3.74
4.90
4.83
3.68
4.10
4.60
4.26
5.08
4.39
48
5
1
1
2a
4a
Cl
Cl MeSO
Cl iPrSO
Cl cyc-PrSO
Cl CNCH SO
HSO
Ac
2
5
1
4b
4c
4d
4e
2b
4f
2
5
1
2
5
1
2
2
6
1
Cl CF
F
2
2
5
1
4.6
5
1
F
F
F
F
F
F
MeSO
EtSO
iPrSO
2
1
1
4g
4h
2
5
2
1
1
1
4i
4j
cyc-PrSO
CF SO
CF HSO
2
1
3
2
2
Interestingly, a divergence in the SAR of the first and second
generation stilbene series was noted when a guanidine unit was
1
4k
2
2
5
2
employed in the R position. While first generation compounds
1
4l
Cl
F
418
401
69
69
4.43
3.91
17
18
(8n) and (8o) displayed Cvyp17 inhibition in the micromolar
range (2500 nM and 1200 nM), the corresponding second
generation compounds (14l) and (14m) were substantially more
potent (17 nM and 18 nM, respectively). A comparison and
overlay of energy minimized structures of (8n) and (14l) (Fig.
1
4m
1
4n
4o
Cl
F
445
429
41
41
4.76
4.25
5
5
1
)
3
4
provided a possible explanation. While there is significant
degree of overlap between (8n) and (14l), it is clear that the
nitrogen atoms in the heteroaromatic rings do not occupy a
similar position in space. It is possible that this change in atomic
display provides the pyridine ring of (14l) with better
opportunities for energetically favorable binding interactions
versus the imidazole ring of (8n).
1
*
TPSA = topological polar surface area, **n = 3
In an effort to expand the utility of our newly discovered
stilbene-based Cyp17 inhibitors, we attempted to replace the
imidazole of COR-003 (6) and (6a) with a pyridine ring.
comparison of the energy minimized structure of COR-003 (6)
A

ACCEPTED MANUSCRIPT
Table 3 Expanded in vitro assessment of exemplary CYP17
inhibitors COR-003, (12b), (14g), and 14j
Tmax (h)
0.1
6
3
6
0.15
5.7
5.33
4.8
0.2
5
3.33
5.25
N/A
t
1/2 (h)
CYP17 CYP19 CYP3A4 CYP3A4/ CYP19/ GPLM**
Entry
IC50 (nM)*
Vd (L/kg)
14.8
N/A
4.05
N/A
9.1
CYP17 CYP17
t
1/2 (min)
Cl
(mL/min/kg)
AUC0-inf
2
8.5
86
N/A
8.79
N/A
20.9
N/A
4
8
1600
146
695
3
33
40
COR-003
5
10000
10000
1000
151
49
2174
2000
167
60
1489
0
1
1
2b
4g
5
2000
N/A
4190 815
22.3 N/A
2452
22.1
(
ng·h/mL)
5
2
243
60
%F
N/A 184.2
1
4j
9360
1560
60
*IV vehicle: 20%DMA, 40%TEG, 40%Water. PO vehicle: 98%
HPMC (1% in water), 2% Tween80.
*
n = 3, **GPLM = guinea pig liver microsome
In order to identify compounds that might be suitable for
advancement into in vivo pharmacokinetic and efficacy studies,
we expanded our in vitro screening studies on key compounds.
We were particularly concerned with off-target activity against
CYP3A4 and CYP19, as well as guinea pig liver microsome
ACKNOWLEDGMENT
We would like to thank the dean of Temple University School
of Pharmacy, Peter
H
Doukas, for his support and
(
GPLM) stability Our original lead compound (COR-003)
displayed limited selectivity over CYP3A4 (IC50 = 146 nM), a
key metabolic enzyme known to be linked to drug/drug
interactions. We believed that increasing this selectivity window
would be advantageous in follow-on compounds advancing
towards clinical exploration. Selectivity over Aromatase was
also viewed as critical. This enzyme plays an important role in
the biosynthesis of estrogen, and interference in this process
would be a significant issue. Finally, our in vivo efficacy models
employ guinea pigs to monitored changes in cortisol synthesis,
and as a result GPLM stability could be used as a predictive tool
to identify compounds capable of sustained systemic exposure
upon dosing. As noted in Table 3, exemplary compounds
selected for advancement (12b, 14g, and 14j) demonstrated
improved selectivity over CYP3A4 (49 fold to 1560 fold) and
CYP19 (167 to 2174 fold). Excellent GPLM stability was also
observed, as all three examples demonstrated t1/2 values of 60
minutes.
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
provided by Strongbridge Biopharma plc, 900 Northbrook
Drive, Suite 200, Trevose, PA 19053 United States. Prior to
th
September 4 , 2015, Strongbridge Biopharma plc was known as
Coretendo plc.
References and notes
1
th
Biochemistry, 8 edition, Berg, J. M.; Tymoczko, J. L.; Gatto, G. J. Jr.
Stryer, L. W. H. Freeman, New York, New York, 2015.
2
Welles, B. Glucocorticoids in type 2 diabetes mellitus and the metabolic
syndrome, Drug Dev. Res. 2006, 67, 570–573.
3
(a) Alex, A. B.; Pal, S. K.; Agarwal, N. CYP17 inhibitors in prostate
cancer: latest evidence and clinical potential, Therapeutic Advances in
Medical Oncology, 2016, 8, 4, 267-275. (b) Johnston, S. R. D.; Dowsett, M.;
Nature Reviews Cancer, 2003, 3, 821-831.
Given the positive results observed in our second tier in vitro
assessment, we advanced (12b), (14g), and (14l) into preliminary
in vivo pharmacokinetic studies using guinea pigs. Compounds
were dosed IV (1 mg/kg) and PO (10 mg/kg) and plasma
concentrations were assessed via LC/MS/MS over a 24 hour
period. As noted in Table 4, all three compounds had moderate
half-lives (4.8 to 6 hours) and systemic exposure (IV and PO)
was well above the CYP17 IC50 values of each compound.
Bioavailability was moderate for (14g) (22.3%) and (14j)
4
(a) Potter, G. A.; Barrie, S. E.; Jarman, M.; Rowlands, M. G. Novel
Steroidal Inhibitors of Human Cytochrome P45017α-Hydroxylase-C17,20-
lyase): Potential Agents for the Treatment of Prostatic Cancer, Journal of
Medicinal Chemistry, 1995, 38, 13, 2463-2471. (b) Abiraterone acetate
(
Zytiga) Reference: Logothetis, C. J.; Efstathiou, E.; Manuguid, F.;
Kirkpatrick, P. Abiraterone acetate, Nature Reviews Drug Discovery, 2011,
0, 8, 573-574.
1
5
(a) Rafferty, S. W.; Eisner, J. R.; Moore, W. R.; Schotzinger, R. J.;
Hoekstra, W. J. Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-
lyase inhibitors, Bioorganic & Medicinal Chemistry Letters, 2014, 24, 11,
(
22.1%), but the higher than predicted oral exposure for (12b)
2
444-2447. (b) Clinical trials: Phase 2: NCT02445976, NCT02130700
(a) Bock, M. G.; Gaul, C.; Gummadi, V. Rao; Sengupta, S. Preparation of
disubstituted imidazolidinone derivatives as cytochrome P450, 17α-
6
(AUC = 14890 ng·h/mL, %F = 184.2%) is indicative of non-
linear pharmacokinetics. It remains unclear why (12b) behaves
in this manner, and will likely prevent this compound from
progressing into advanced in vivo efficacy studies.
hydroxylase, c17-20 lyase inhibitors WO2010149755, 2010. (b) Clinical
trials: Phase 2 NCT01647789
7
(a) Koziol, T. R. Methods and compositions for the treatment of Cushing's
Syndrome using 2S,4R-ketoconazole, WO2016048984A1, 2016. (b) Clinical
In summary, we have identified two novel series of stilbene
derivatives capable of inhibiting CYP17, a key enzyme in the
cortisol synthetic pathway and a validated target in prostate
cancer therapy. Exemplary compounds examined in this series
possess in vivo pharmacokinetic properties suitable for in vivo
efficacy studies to determine their potential for therapeutic utility.
The results of these studies are will be reported separately.
trial for Endogenous Cushing's Syndrome, NCT01838551, phase 3.
8
Hakki, T.; Bernhardt, R. CYP17- and CYP11B-dependent steroid
hydroxylases as drug development targets, Pharm. Thera. 2006, 111, 1, 27-
52.
9
Blass, B. E.; Iyer, P.; Abou-Gharbia, M.; Childers, W. E.; 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. Bioorg Med Chem
Lett. 2016, 26, 23, 5825-5829..
Table 4: Guinea pig in vivo pharmacokinetic profiles of
exemplary stilbene derivatives.
10
Energy minimizations were conducted with the Tripos
Benchware 3D Explorer software package.
(
n = 3)
12b
14g
14j
Dose(mg/kg)
Delivery*
1
10
PO
1
10
PO
540
1
10
PO
271
11
cLogP and TPSA values were calculated using the
Dotmatics Browser software suite.
IV
IV
IV
1
2
Energy minimizations were conducted with the Tripos
Benchware 3D Explorer software package.
Cmax(ng/mL)
132
1018
852
203

ACCEPTED MANUSCRIPT
13
Energy minimizations were conducted with the Tripos
Benchware 3D Explorer software package.

ACCEPTED MANUSCRIPT
Highlights for article entitled “Design and synthesis of functionalized piperazin-1yl-(E)-stilbenes
as inhibitors of 17α-hydroxylase-C17,20-lyase (Cyp17).”
1) Cyp17 (17α-hydroxylase-17,20-lyase) is a validated prostate cancer target.
2) Novel stilbenes disclosed herein are potent, selective inhibitors of Cyp17.
3) In vivo PK studies indicate that members of this class are orally bioavailable.