Potent and selective small-molecule human urotensin-II antagonists with improved pharmacokinetic profiles

Article abstract of DOI:10.1016/j.bmcl.2008.05.058

Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-

Full text of DOI:10.1016/j.bmcl.2008.05.058

Bioorganic & Medicinal Chemistry Letters 18 (2008) 3716–3719
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Potent and selective small-molecule human urotensin-II antagonists with
improved pharmacokinetic profiles
a
a
f
a
John J. McAtee a, , Jason W. Dodson , Sarah E. Dowdell , Karl Erhard , Gerald R. Girard ,
Krista B. Goodman a, Mark A. Hilfiker a, Jian Jin a, Clark A. Sehon a, Deyou Sha a, Dongchuan Shi a,
Feng Wang d, Gren Z. Wang a, Ning Wang a, Yonghui Wang f, Andrew Q. Viet a, Catherine C. K. Yuan a,
Daohua Zhang a, Nambi V. Aiyar b, David J. Behm b, Luz H. Carballo e, Christopher A. Evans c, Harvey E. Fries c,
Rakesh Nagilla c, Theresa J. Roethke c, Xiaoping Xu b, Stephen A. Douglas b, Michael J. Neeb a
*
a Department of Medicinal Chemistry, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road,
PO Box 1539, King of Prussia, PA 19406, USA
b Department of Biology, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia,
PA 19406, USA
c Drug Metabolism and Pharmacokinetics, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road,
King of Prussia, PA 19406, USA
d Molecular Discovery Research, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
e Screening and Compound Profiling, Research Triangle Park, 4117 Emperor Boulevard, Morrisville, NC 27703, USA
f Oncology Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, Collegeville, PA 19426, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic
profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-
phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in com-
pound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between ste-
Received 18 April 2008
Revised 9 May 2008
Accepted 15 May 2008
Available online 20 May 2008
reochemistry and selectivity for hUT over the
j
-opioid receptor was also explored.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Urotensin
HUT
HUT-II
UT
GPR-14
Antagonist
7-TM
7-Transmembrane
Human urotensin-II (hU-II), a cyclic undecapeptide, has been
identified as a powerful vasoconstrictor.1,2 In 1999, hU-II was iden-
tified as a cognate ligand of human GPR-14 (hUT), an ‘orphan’ 7-TM
receptor predominantly expressed in vascular and cardiac tissue.2
hU-II and hUT are thought to be involved in the (dys)regulation
of cardiorenal function,3 and have been implicated in the etiology
of numerous cardiorenal and metabolic diseases including hyper-
tension,4 heart failure,5,6 atherosclerosis,7 renal failure,8 and diabe-
tes.9 Several non-peptidic UT ligands have recently been
reported.10 hUT antagonists are of interest as potential drugs to ad-
dress these cardiorenal and metabolic conditions.
Recently, we reported the development of potent and selective
hUT antagonists based on the 2-pyrrolidinylmethyl-3-phenyl-
piperidine core of 111 (Table 1). Within this ‘piperidine-core’ series,
lead optimization led to several improvements to compound 1 in
terms of hUT-binding affinity (Ki)11,12 and selectivity against the
j
-opioid receptor,11 the NaV1.5 cardiac sodium channel,11 the rat
brain batrachotoxinin (BTX) sensitive sodium channel,11 and
P450 inhibition for CYP2D6. However, the rat pharmacokinetic
profile of these compounds remained poor, especially with regard
to oral bioavailability. In addition, CYP3A4 inhibition was still gen-
erally problematic for this chemical series. In seeking a structural
modification that might allow for a new direction in lead optimiza-
tion, a strategy was designed which incorporated two elements.
The first element of the strategy explored potential structural
and synthetic simplifications to the amide–amine–aryl structural
* Corresponding author. Tel.: +1 610 270 6822; fax: +1 610 270 4490.
E-mail addresses: jeff.j.mcatee@gsk.com, jmcatee4@juno.com (J.J. McAtee).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.058

J. J. McAtee et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3716–3719
3717
Table 1
H3C
O
Stereochemical comparison of chemical series
N
OH
OH
CH3 OH
N
Cl
Cl
N
Cl
Cl
Cl
Cl
N
O
O
O
Cl
N
N
Cl
N
N
Cl
Cl
N
N
A
B
C
N
O
Cl
Cl
N
O
O
OH
OH
OH
O
O
O
O
7 (
S
) enantiomer
1-3
4-6
O
O
N
Cl
Cl
N
O
H3C
H3C
N
N
R
b
Compound
Stereochemistry
hUT Kia (nM)
Kappa EC50 (nM)
O
R
1
2
3
4
5
6
7
Racemate
(R,R)
(S,S)
Racemate
(R)
16
6
1600
15
13
3200
6300
2000
0.2
D
E
F (R = Cl)
G (R = CH3)
Fig. 1. Acid precursors to side-chain amide groups.11
4
(S)
(S)
2500
4000
0.1
0.4
a
Although these data suggested that the (R) stereochemistry
Means of at least two determinations with a standard deviation of < 0.3 log
would be advantageous for both hUT-binding affinity and for
units.
b
Single determination or a mean of two determinations with a standard devia-
tion of < 0.3 log units.
selectivity against the
j-opioid receptor, initial SAR develop-
ment was performed with racemic compounds for ease of syn-
thesis. Follow-up of selected analogs as the (R) enantiomer to
maximize selectivity over the
j-opioid receptor would then be
motif highlighted in structure 1 (Table 1). Lead optimization of the
piperidine-core series11 established that a basic amine linked to an
amide group as in compound 1 was essential for hUT-binding affin-
ity in this chemical series. Analogs with the pendant phenyl ring
had significantly greater hUT-binding affinity than those lacking
a phenyl ring.11 Based on this information, compound 4 was pro-
posed as an alternative scaffold, which shares the amide–amine–
aryl structural motif with 1, but has one less stereocenter and is
more synthetically accessible. The second element of the strategy
involved several observations related to the stereochemistry of
the piperidine core template (1–3) as it relates to hUT-binding
pursued if necessary. Adding a phenyl ring to 4 (Fig. 2) to gen-
erate the biphenyl analog 8 resulted in a compound with signif-
icantly reduced CYP2D6 inhibition and an 80-fold reduction in
j
-opioid agonism (Table 2). However, 8 still retained sodium
channel activity.11d Interestingly, some of the SAR trends that
were observed in the piperidine core series11 were also ob-
served in the ethane-diamine series. It was found that replacing
the pyrrolidine moiety of 8 with a morpholine group (com-
pound 9) resulted in several improvements in the in vitro pro-
file: reduced sodium channel activity, a 100-fold reduction in
j-opioid agonist potency, and reduced CYP2D6 inhibition. How-
affinity and j-opioid receptor agonism. In the piperidine-core ser-
ever, hUT-binding affinity dropped by more than 30-fold with
this change. It was also observed that hUT-binding affinity could
be regained by employing one of the improved amide groups11
(Fig. 1) as exemplified by compound 10. The opposing stereo-
ies, (R,R) enantiomer 2 was found to have more than 200-fold high-
er binding affinity for hUT than the (S,S) enantiomer 3.11
Interestingly,
j-opioid receptor agonism exhibited the opposite
stereochemical trend with the (S,S) enantiomer being the more ac-
tive one. At the same time, exploration of the chemical literature
revealed that compounds such as 7 based on a substituted N-
methyl-2-(1-pyrrolidinyl)ethanamine core (referred to herein as
the ‘ethane-diamine core’ for convenience) have been previously
reported as j
-opioid agonists.3,14 The importance of the (S) stereo-
Improvement
in P450
chemistry for kappa receptor agonism in compound 7 and struc-
turally related analogs has been demonstrated.13,14 The fact that
compound 7 shares the amide–amine–aryl structural motif with
1 and also exhibits a stereochemical preference for the (S) enantio-
H3C
CH3
N
N
H3C
CH3
N
N
N
N
Cl
Cl
O
Cl
Cl
O
8
mer with regard to
j-opioid agonism prompted the evaluation of
4
whether or not the same stereochemical trends in orthogonal
j-
opioid agonism and hUT antagonism held for the ethane-diamine
core series. If true, then the (R) stereochemistry in compounds con-
taining the ethane-diamine core should provide hUT antagonists
- Loss of some hUT Ki
- Improvement in Na
channel and Kappa
opioid selectivity
with selectivity over the
j-opioid receptor. Together, pharmaco-
phore-driven rational design and the stereochemical observations
from the chemical literature led to the discovery of compound 5
with an ethane-diamine core as a potent urotensin antagonist Ta-
ble 1.
Compounds 5 and 6 were obtained by chiral HPLC separation of
the racemate 4. While (R) enantiomer 5 was the more potent hUT
O
H3C
N
N
O
H3C
CH3
N
O
O
N
Restoration
of hUT Ki
N
Cl
Cl
N
O
Cl
Cl
O
antagonist,
enantiomer 6. Although 5 remained a potent kappa agonist (4 nM),
the separation between hUT and activity for these enantiomers
j receptor agonism resided predominantly with the (S)
9
10 Racemate
j
11 (R) enantiomer
12 (S) enantiomer
provided confidence that further optimization might identify a
compound with acceptable selectivity for progression (Fig. 2 and
Table 2).
Fig. 2. Initial optimization of ethane-diamine core analogs.

3718
J. J. McAtee et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3716–3719
Table 2
Optimization of ethane-diamine core analogs
Compound
In vitro data
b
d
hUT Kia (nM)
Kappa EC50 (nM)
Na channel Kia,c (nM)
CYP 2D6 IC50
(l
M)
CYP 3A4 DEF IC50d. (
lM)
1
4
8
16
15
20
630
13
3200
0.2
16
1600
320
800
40
2500
0.75
0.16
5.9
16
33
33
1.4
3.3
4.9
2.1
4.6
9.1
4.2
NAe
1200
9
>30,000
11,130
7700
10
11
12
16
630
9400
33
a
Means of at least two determinations with a standard deviation of < 0.3 log units.
Single determination or a mean of two determinations with a standard deviation of < 0.3 log units.
Rat brain batrachotoxinin (BTX)-sensitive sodium channel assay.
Single determination, Cypex Bactosomes.
Na channel data ARE not available for 7, but for (R)-4, Na channel Ki = 2000 nM.
b
c
d
e
Table 3
Further development of the ethane-diamine series
R2
H3C
N
N
R1
b
d
d
Compound
R1
R2
Amine
hUT Kia (nM)
Kappa EC50 (nM)
Na Channel Kia,c (nM)
CYP 2D6 IC50
(l
M)
CYP 3A4 DEF IC50
(l
M)
13
14
15
16
17
18
G
C
B
F
E
D
3-CONH(CH3)
4-CONH2
3-CONH2
3-CONH(CH3)
4-NHCOCH3
3-OCH3
Morpholine
Pyrrolidine
Pyrrolidine
Morpholine
Morpholine
Morpholine
6
3
0.3
4
3
4000
100
32
2000
800
160
30,000
17,000
22,000
30,000
30,000
22,000
33
6.2
3.5
33
30
17
9
2.6
2.2
5
6.4
1
5
a
Means of at least two determinations with a standard deviation of < 0.3 log units.
b
c
Single determination or a mean of two determinations with a standard deviation of < 0.3 log units.
Rat brain batrachotoxinin (BTX)-sensitive sodium channel assay.
Single determination, Cypex Bactosomes.
d
Table 4
chemical SAR trends for hUT-binding affinity and
ism are also valid for this new biphenyl-ethanediamine series,
j-opioid agon-
Rat PK data for representative analogs
as shown by the divergent profiles of 11 and 12. Indeed, the
Compound
PK dataa
(R) enantiomer 11 is 50-fold selective for hUT over the
j-opioid
Cmax (ng/mL) T1/2 (h) CL (mL/min/kg) Vdss (L/kg) Oral F (%)
receptor.
1
10
11
12
13
15
16
17
18
100
160
200
230
890
340
1100
600
290
3.8
2.4
2.2
2.6
1.0
3.4
1.5
1.7
3.4
97
23
23
11
19
1.7
20
2
0-3
44
43
17
39
36
29
83
30
Further development of this compound series focused on varia-
tions in the substituents of the distal ring of the biphenyl group,
exploration of different side-chain amides, and utilization of either
the pyrrolidine or morpholine moieties as the basic amine group.
Table 3 summarizes the in vitro profiles of representative examples.
It was noted that polar functional groups on the distal ring suffi-
ciently improved selectivity for hUT over the sodium channel such
that even pyrrolidine analogs were still highly selective. Thus,
biphenyl amide 15 has acceptable selectivity over the sodium chan-
nel and has improved binding affinity (40-fold) compared to com-
pound 10. Even as racemates, several of these analogs such as 13,
150
120
130
60
100
36
94
140
2.8
20
a
Rat PK data based on 2 mg/kg iv dose and 4 mg/kg solution oral dose.
except half-life were improved relative to the piperidine core ser-
ies.11 One important result with this series was the general reduc-
tion in the volume of distribution compared to the piperidine core
series. In several cases, such as compounds 13, 16, and 17 the vol-
ume of distribution was an order of magnitude lower than the
average for the piperidine core analogs. Since the urotensin recep-
tor population that is relevant to blood pressure regulation is pri-
marily expressed in the vascular smooth muscle, compounds
with a high volume may be less desirable than low-to-moderate
volume compounds. Interestingly, stereochemistry did not seem
to affect the pharmacokinetic profile to the extent that it influ-
15, and 17 demonstrate selectivity against the
j-opioid receptor
that exceeds that of the (R) enantiomer 11. Furthermore, these
improvements were achieved without any degradation of the
P450 profile. Most significant was the finding that the pharmacoki-
netic profile for the ethane-diamine series is substantially improved
over the original piperidine-core series (Table 4). In addition, these
compounds are functionally potent in the rat aortic ring contraction
assay15 at levels comparable to the in vitro rat binding affinity. For
example, compound 18 has a rat aorta Kb of 21 nM.
While the greatest overall improvement was achieved with re-
gard to oral bioavailability, it was possible to identify compounds
such as 13 and16 in which all of the pharmacokinetic parameters
enced hUT-binding affinity or j-opioid agonism. There was little
difference in the rat pharmacokinetic profiles of the (R) enantiomer
11 or the (S) enantiomer 12 compared to the racemate 10.

J. J. McAtee et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3716–3719
3719
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11. (a) Jin, J.; Wang, Y.; Wang, F.; Shi, D.; Erhard, K.; Wu, Z.; Guida, B. F.; Lawrence,
S. K.; Behm, D. J.; Disa, J.; Vaidya, K. S.; Evans, C.; McMillan, L. J.; Rivero, R. A.;
Neeb, M. J.; Douglas, S. A. Bioorg. Med. Chem. Lett. 2008, 18, 2860; (b) McAtee, J.
J.; Dodson, J. W.; Dowdell, S. E.; Girard, G. R.; Goodman, K. B.; Hilfiker, M. A.;
Sehon, C. A.; Sha, D.; Wang, G.; Wang, N.; Viet, A.; Zhang, D.; Aiyar, N.; Behm, D.
J.; Carballo, L. H.; Evans, C. A.; Fries, H. E.; Nagilla, R.; Roethke, T. J.; Xu, X.; Yuan,
C. K.; Douglas, S. A.; Neeb, M. J. Bioorg. Med. Chem. Lett. 2008, 18, 3500; for
details of the sodium channel assay, see: (c) Shimidzu, T.; Itoh, Y.; Tatsumi, S.;
Hayashi, S.; Ukai, Y.; Yoshikuni, Y.; Kimura, K. Nanyn-Schmiedeberg’s Arch.
R2
Br
Br
iii, iv
i, ii
X
N
X
Br
N
R1
O
H
O
19 X = pyrrolidine
20 X = morpholine
Scheme 1. Reagents and conditions: (i) pyrrolidine or morpholine, ether, 96%; (ii)
CH3NH2, CH3COOH, NaBH3(CN), THF, 99%; (iii) carboxylic acid from Figure 1, BOP
reagent, Et3N, DMF, 70–90%; (iv) phenyl boronic acid, 1 M Na2CO3, Pd(dppf)Cl2,
dioxane, 160 °C, microwave, 360 s, 20–70%.
To prepare the diamine core for this series, 2,40-dibromoaceto-
phenone was treated with either morpholine or pyrrolidine to give
a high yield of the
a-amino ketones, which were subjected to
reductive amination with methylamine to give ethane-diamine
intermediates 19 and 20. Amide coupling of the side-chain acid
groups (syntheses reported in a previous publication11) shown in
Figure 1 to either 19 or 20 yielded the aryl bromide intermediates
for the Suzuki coupling in the final step (Scheme 1). The (R) and (S)
enantiomers, 11 and 12, respectively, were obtained by chiral HPLC
separation of racemic 10.
In summary, replacing the piperidine core of lead compound 1
with the substituted ethane-diamine core resulted in compounds
with superior pharmacokinetic profiles, particularly with regard
to the improved oral bioavailability. It was discovered that the ste-
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j-opioid receptor assay, see: (d)
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j-opioid
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j
-opioid receptor, and a developable pharmacokinetic profile.
Many of these compounds have good selectivity over the
j
-opioid
receptor even as the racemates, but compounds such as 14 and 15
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could be further improved by capitalizing on this stereochemical
differentiation in hUT and
j activity via the synthesis of the R
enantiomer of each of these compounds.
References and notes
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