Quinolines as extremely potent and selective PDE5 inhibitors as potential agents for treatment of erectile dysfunction

Article abstract of DOI:10.1016/j.bmcl.2003.12.090

In a continuing effort to discover novel chemotypes as potent and selective PDE5 inhibitors for the treatment of male erectile dysfunction (ED), we have found that 4-benzylaminoquinoline derivatives are very potent and selective PDE5 inhibitors. Some compounds in this series had PDE5 IC ₅₀'s as low as 50 pM. While an electron withdrawing group at the C6-position of the quinoline substantially improved PDE5 potency, an ethyl group at the C8-position not only improved the PDE5 potency but also the isozyme selectivity. Substitutents at the C3-position can incorporate a variety of different groups. The synthesis and primary structure-activity relationship of this new series of potent PDE5 inhibitors are described.

Full text of DOI:10.1016/j.bmcl.2003.12.090

Bioorganic & Medicinal Chemistry Letters 14 (2004) 1577–1580
Quinolines as extremely potent and selective PDE5 inhibitors as
potential agents for treatment of erectile dysfunction
Yingzhi Bi,a,* Patrick Stoy,a Leonard Adam,b Bin He,b John Krupinski,b
Diane Normandin,b Ron Pongrac,b Laurie Seliger,b Andrew Watsonc and John E. Macora
aDepartment of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400,
Princeton, NJ 08543-5400, USA
bDepartment of Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute,
PO Box 5400, Princeton, NJ 08543-5400, USA
cDepartment of Oncology and Immunology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute,
PO Box 5400, Princeton, NJ 08543-5400, USA
Received 29 October 2003; accepted 16 December 2003
Abstract—In a continuing effort to discover novel chemotypes as potent and selective PDE5 inhibitors for the treatment of male
erectile dysfunction (ED), we have found that 4-benzylaminoquinoline derivatives are very potent and selective PDE5 inhibitors.
Some compounds in this series had PDE5 IC50’s as low as 50 pM. While an electron withdrawing group at the C6-position of the
quinoline substantially improved PDE5 potency, an ethyl group at the C8-position not only improved the PDE5 potency but also
the isozyme selectivity. Substitutents at the C3-position can incorporate a variety of different groups. The synthesis and primary
structure–activity relationship of this new series of potent PDE5 inhibitors are described.
# 2004 Elsevier Ltd. All rights reserved.
Viagra1 (sildenafil, 1a, Fig. 1) has been shown to be an
effective therapy for the treatment of erectile dysfunc-
tion (ED) in men.1 Discovered serendipitously, sildenafil
acts as an inhibitor of phosphodiesterase Type 5
(PDE5) in the corpus cavernosum of the penis, effectively
elevating the levels of cGMP in that tissue. Increased
levels of cGMP leads to decreased intracellular calcium
in the cells of the corpus cavernosum, resulting in
relaxation of the smooth muscle of the penis. This
relaxation results in enhanced arterial blood flow into
the penis, ultimately leading to an erection.2
have been noted, and their incidence increases with the
dose of the drug. Certain of these adverse events are
thought to be due to nonspecific inhibition of other
PDEs, specifically PDE1 and PDE6.3,4 Thus, the iden-
tification of more potent and more selective PDE5 inhi-
bitors is of substantial medicinal and commercial
Sildenafil (1a), the prototypical (PDE5) inhibitor, has
opened an entire field of drug discovery focused on dis-
eases which affect one’s quality-of-life, and the treat-
ment of male erectile dysfunction (ED) is one of those
areas. In spite of the efficacy of 1a as a treatment for
ED, there are notable drawbacks associated with its use.
Clinically significant adverse effects such as nausea,
headache, cutaneous flushing and visual disturbances
* Corresponding author at current address: Lexicon Pharmaceuticals,
350 Carter Road, Princeton, NJ 08540, USA. Tel.: +1-609-466-
5566; fax: +1-609-466-3562; e-mail: ybi@lexpharma.com
Figure 1.
0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.12.090

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Y. Bi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1577–1580
interest. Therefore, it is not surprising that significant
effort has been expended towards the discovery of more
isozyme selective PDE5 inhibitors.5,6 In this communi-
cation, we detail our continued efforts in this area,7ꢀ9
which have yielded a new series of picomolar potent and
selective PDE5 inhibitors.
and selectivity in all of these series. Follow-up work at
Pfizer with sildenafil also apparently found a similar
effect from a ‘northern benzyl’ group when attached to
the heterocyclic scaffold of sildenafil (1b).10
As part of our continuing effort to discover novel
chemotypes as potent and selective PDE5 inhibitors for
the treatment of ED, we decided to explore combinations
of key functional groups in recently discovered inhibi-
tors. Combining the important features of the two potent
PDE5 inhibitors 4 (BMS) and 5 (Eisai) led to the design
of the quinoline derivatives (6, Scheme 1).11 To test this
combination hypothesis, quinoline 6a was prepared in
two steps from commercial available starting materials
(Scheme 2). The hydroxyl group in compound 10a
(R6=R8=H, R7=CF3) was converted to the corres-
ponding chloride by reflux in POCl3. The chloride was
then displaced by 3-chloro-4-methoxybenzyl amine to
Rotella and co-workers7 have described a series of N-3
substituted imidazoquinazolinones (2, Fig. 1) as potent
and selective PDE5 inhibitors. We have also reported
on a series of novel pyrazolopyridopyrimidines (3, Fig.
1) that provided PDE5 inhibitors which were more
potent and selective than sildenafil.8 More recently, Yu
et al.9 reported substituted pyrazolopyridines as potent
and selective PDE5 inhibitors (4, Scheme 1). Use of an
appropriately substituted benzylamino moiety placed in
the ‘northern’ region of the scaffolds consistently con-
ferred substantial improvement in both PDE5 potency
Scheme 1.
Scheme 2. (a) Toluene, reflux, 4 h (70–90%); (b) Ph2O, reflux, 2 h (70–95%); (c) POCl3, reflux, 24–48 h (70–100%); (d) 3-chloro-4-methoxybenzyl
ꢁ
.
amine HCl, DIEA/n-PrOH, reflux, 2 h (40–95%); (e) NaOH (1 N)/MeOH, rt, 1 h (>90%); (f) Ph2O, 240 C, 30 min, (75%); (g) 1. DCC/EtOAc,
pentafluorophenol/DMF, rt, 18 h; 2. NHRR0/DMF, 18 h (>60%); (h) LiAl(OtBu)3H/THF, reflux, overnight (50–90%). All compounds were
characterized minimally by 1H and 13C NMR, LCMS, HPLC and HRMS.

Y. Bi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1577–1580
1579
give 6a. This benzylamine was consistently the best
moiety in many of our PDE5 inhibitors.7ꢀ9 Our combi-
nation hypothesis was supported as compound 6a was a
selective PDE5 inhibitor (PDE5 IC50=160 nM, PDE6
IC50=20 mM, IC50 >50 mM for PDE1-4).
PDE5 inhibitory activity by about 20-fold (PDE5
IC50=4.0 nM) with excellent PDE isozyme selectivities
against PDEs 1–4 (Table 1). Because our hypothesis to
merge the structures of PDE5 inhibitors 4 and 5 led to a
new scaffold for potent and selective PDE5 inhibition,
we sought to further capitalize on this SAR overlap and
incorporate the N-ethyl group in the pyrazolopyridines
4. This line of reasoning afforded quinoline 6g which
was almost 10-fold more potent than its des-ethyl ana-
logue 6c. Compounds 6c and 6g provided ideal scaffolds
for additional structure activity development. We
explored modifications of the ester at C3 of the quino-
line moiety in an attempt to improve isozyme selectivity
and PDE5 potency.
The chemistry to provide analogues of 6a is shown in
Scheme 2, and their in vitro results are shown in Table 1.
The appropriate anilines 7 were converted to 9 by
refluxing in toluene with ethoxymethylenemalonate 8.
Cyclization of 9 in refluxing diphenylether afforded
quinolines 10 in good yields. Reaction of 10 with POCl3
afforded the chloroquinolines 11 often in quantitative
yield. Reaction of quinolines 11 with 3-chloro-4-meth-
oxybenzyl amine afforded the quinoline esters 6a–c and
g. Reduction of the ester in 6c (R6=–CN, R7 and R8=
–H) and 6g (R6=–CN, R7=–H, and R8=–Et) to the
hydroxymethyl derivatives afforded 6f and j, respec-
tively (Table 1). Alternatively, hydrolysis of the ester in
6c and 6g afforded the carboxylic acids 12c and 12g.
Decarboxylation of these acids at elevated temperatures
afforded 6d (R6=–CN, R7 and R8=–H) and 6h
(R6=–CN, R7=–H, and R8=–Et), respectively. The
acids 12c and 12g were also converted to amides via
their pentafluorophenyl esters to afford quinoline amides
6e (R6=–CN, R7 and R8=–H) and 6i (R6=–CN, R7=
–H, and R8=–Et), respectively (Table 1).
We were delighted to observe that the C-3 position was
quite tolerant to varied substitution. Ester (6c and g),
hydrogen (6d and h), amide (6e and i) and alcohol (6f
and j) moieties all maintained excellent PDE5 potency
and PDE 1-4 selectivity with moderate-to-good PDE6
selectivity (Table 1). In all cases, incorporation of a C8
ethyl group into our quinoline template to mimic the
ethyl group in 4 resulted in a moderate (up to 10-fold),
but significant increase in PDE5 potency compared to
the C8 unsubstituted quinoline analogue. This modifi-
cation also led to compounds with improved PDE5
potency and isozyme selectivities. Of special note is the
C3-hydroxymethyl analogue (6j, Table 1). We believe
that compound 6j represents the most potent and selec-
tive PDE5 inhibitor seen to date (PDE5 IC50=50 pM).
Compound 6j is not only more than 30-fold more
potent than sildenafil, it is significantly more selective
against other PDE isozymes than sildenafil, especially
against PDE6. This would suggest that 6j would represent
a drug that would be devoid of any clinical side effects
which result from inhibition of PDEs 1–4 or PDE6.
Moving the trifluoromethyl group from C7 to C6 on the
quinoline scaffold led to compound 6b, and this modifi-
cation resulted in a slight improvement in PDE5 inhibi-
tion (Table 1). This SAR observation was analogous to
that described by Watanabe et al. in the development of
5.12 Led by this SAR, we next explored the cyano ana-
logue of 6b. Introduction of the C6 cyano group in the
quinoline scaffold provided 6c and further improved
Table 1. PDE5 potency and selectivity ratios for other PDEsa,b,c
PDE5
Ratio (PDE X/PDE5)
3
Compd
R3
R6
R7
R8
IC50 (nM)
1
2
4
6
Sildenafil
—
COOEt
COOEt
COOEt
H
—
H
CF3
—
CF3
H
—
H
H
4.0
1.4
1.3
0.48
0.60
0.40
0.55
0.05
1.6ꢂ0.5
160ꢂ80
73ꢂ41
ꢂ2.1
140
>310
>680
>104
6400
>104
>104
>104
>104
>104
>105
>104
>310
>680
>104
>104
>104
8600
>104
>104
>104
>104
3500
>310
>510
>104
2900
>104
>104
>104
>104
>104
>105
2600
>310
247
8
125
75
15
29
64
23
110
40
82
7800
6a
6b
6c
6d
6e
6f
6g
6h
6i
CNH
CNH
CNH
CNH
CNH
CNH
CNH
CNH
H
H
H
3800
3500
3100
>104
>104
2200
4500
>104
ꢂ0.9
CONHCH22-Py
CH2OH
COOEt
ꢂ0.7
H
ꢂ0.04
ꢂ0.19
ꢂ0.06
ꢂ0.43
ꢂ0.04
Et
Et
Et
Et
H
CONHCH22-Py
CH2OH
6j
a Enzyme sources: PDE1: bovine heart; PDE2: rat kidney; PDE3: human platelet; PDE4: rat kidney; PDE5: human platelet; PDE6: bovine retina.
Enzyme assays performed as described in references 7a and 7b.
b All IC50 determinations are averages based on ꢃ3 determinations and shown as ꢂSD.
c Py=pyridyl.

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Y. Bi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1577–1580
In summary, we have found that the 4-benzylamino-
quinoline scaffold provided very potent and selective
PDE5 inhibitors. Starting from 6a (PDE5 IC50=160
nM), we utilized insight derived from other similar series
to develop a series of potent and selective quinoline
PDE5 inhibitors. In this series, C6-cyano and C8-ethyl
provided the most potent compounds. Substitution at
C3 of the quinoline scaffold could be varied while still
maintaining potent PDE5 inhibition. Our SAR efforts
resulted in the discovery of 6j, which contained a C3-
hydroxymethyl group. Compound 6j is the most potent
and selective PDE5 inhibitor identified to date, being
30-fold more potent than sildenafil and significantly
more selective than sildenafil against other PDE
isozymes. We continue to profile this series of PDE5
inhibitors and will report additional SAR and pharma-
cology in due course.
2. Gibson, A. Eur. J. Pharmacol. 2001, 411, 1.
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4. Scrip, October 9, 1997.
5. Andersson, K.-E.; Wagner, G. Physiol. Rev. 1995, 75, 191.
6. (a) Eardley, I. Exp. Opin. Invest. Drugs 1997, 6, 1803. (b)
Garcia-Reboll, L.; Mulhall, J. P.; Goldstein, I. Drugs &
Aging 1997, 11, 140. (c) Truss, M. C.; Stief, C. G. Drugs of
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Pongrac, R.; Seliger, L.; Normandin, D.; Macor, J. E. J.
Med. Chem. 2000, 43, 1257. (b) Rotella, D. P.; Sun, Z.;
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Normandin, D.; Pongrac, R.; Seliger, L.; Watson, A.;
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potent cGMP specific (PDE) inhibitors was disclosed in a
patent. Umeda, N.; Ito, K.; Uchida, S.; Shiinoki, Y. WO
0112608, 2001.
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