Investigation of the pyrazinones as PDE5 inhibitors: Evaluation of regioisomeric projections into the solvent region

Article abstract of DOI:10.1016/j.bmcl.2011.08.106

We describe the design, synthesis and profiling of a novel series of PDE5 inhibitors. We take advantage of an alternate projection into the solvent region to identify compounds with excellent potency, selectivity and pharmacokinetic profiles.

Full text of DOI:10.1016/j.bmcl.2011.08.106

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6348–6352
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Investigation of the pyrazinones as PDE5 inhibitors: Evaluation
of regioisomeric projections into the solvent region
Robert O. Hughes a, , Todd Maddux a, D. Joseph Rogier a, Sharon Lu a, John K. Walker a, E. Jon Jacobsen a,
⇑
Jeanne M. Rumsey a, Yi Zheng a, Alan MacInnes a, Brian R. Bond a, Seungil Han b
a Pfizer Global Research and Development, 700 Chesterfield Parkway West, St. Louis, MO 63017, USA
b Pfizer Global Research and Development, 100 Eastern Point Road, Groton, CT 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the design, synthesis and profiling of a novel series of PDE5 inhibitors. We take advantage of
an alternate projection into the solvent region to identify compounds with excellent potency, selectivity
and pharmacokinetic profiles.
Received 15 July 2011
Revised 19 August 2011
Accepted 25 August 2011
Available online 31 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
PDE5 inhibitors
Pyrazinones
Lead optimization
Ligand efficiency
Lipophilic efficiency
Expressed in vascular smooth muscle cells phosphodiesterase
type 5 (PDE5) hydrolyzes cGMP to the inactive metabolite 50-GMP.
Over the last decade, significant clinical and commercial experience
has demonstrated the safety, tolerance and efficacy of PDE5 inhibi-
tors, such as sildenafil, for the treatment of male erectile dysfunctio-
non (MED).1 Recently, preclinical studies as well as clinical trials
have suggested that PDE5 inhibitors could be/are effective in the
treatment of various other diseases such as Raynaud’s disease, gas-
trointestinal disorders and stroke.2 Against this backdrop, we initi-
ated a program directed toward the discovery of long-acting,
selective inhibitors of PDE5.
OMe
OPr
N
H
N
O
R
N
N
N
1: R =
3: R =
N
O
H
N
N
2: R =
HO
N
HO
Figure 1. Key 1,3 aminopyrazinone lead structures: advanced lead 1, pre-clinical
candidate 2 and clinical candidate 3.
We recently described the design, synthesis and evaluation of a
series of aminopyridopyrazinones as novel PDE5 inhibitors (Fig. 1).3
Optimization of the pharmacokinetic (PK) profile of advanced lead
compound 1, a highly potent and selective inhibitor of PDE5, led
to cyclohexanol4 2 which had a favorable preclinical PK profile
but attrited during rodent toxicological studies. Subsequent refine-
ment led to the basic piperazine derivative 3 which is currently in
clinical trials.5 Herein, we describe our efforts to further examine
the SAR of this series of compounds and develop alternate ap-
proaches to effectively balance the potency, selectivity and PK pro-
files. Examination of crystal structure of 1 (Fig. 4) bound to PDE5
suggested the geometric isomers envisioned in Figure 2 would pro-
ject substituents into the solvent region and be well tolerated from
1,3 Isomer
1,4 Isomer
OPr
OMe
OMe
OPr
N
O
N
N
O
N
R1
N
N
N
N
N
R2
1N
R
R2
Solvent Region
Figure 2. Proposed, novel 1,4 isomer compared to the 1,3 isomer. The southeastern
pyridine6 version of both cores is illustrated.
the potency perspective. Furthermore, we speculated that the 1,4
relationship between the propyloxy ether and the solvent region
may confer improved solubility as compared to the 1,3 derived
compounds.
⇑
Corresponding author.
E-mail address: robowenhughes@gmail.com (R.O. Hughes).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.08.106

R. O. Hughes et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6348–6352
6349
R1
O
R1
R2HN
EtO
Cl
Cl
MeO
Cl
R2HN
Cl
b
h, i
N
N
EtO
H2N
O
N
N
O
O
4: R1 = OH
5: R1 = Cl
6
12
13
a
c
j
R2
R2
OMe
OMe
R2HN
Cl
O
N
R5
R2HN
N
e
g
O
HN
N
Cl
k
R1
N
N
N
N
H2N
O
N
NR3R4
O
O
9
7: R1 = OH
8: R1 = NH2
15: R5 = Cl
d
l
14
OMe
16: R5 =
f
N
OMe
R2
N
R2
O
N
O
N
N
N
N
HN
N
NR3R4
O
11
10
Scheme 1. Reagents and conditions: (a) POCl3, 100 °C; (b) R2NH2, dichloroethane, 23 °C; (c) LiOH, 1,2-dimethoxyethane, water, 23 °C; (d) SOCl2, cat. DMF, CH2Cl2, 23 °C then
NH4OH (aq), 23 °C; (e) 6-methoxypyridin-3-ylboronic acid, Pd(Ph3P)4, Na2CO3, dioxane, water, reflux; (f) NaH, di(1H-imidazol-1-yl)methanone, DMF, 0?75 °C; (g) POCl3,
100 °C then R3R4NH, CH2Cl2, 23 °C; (h) 7 N NH3, MeOH, 23 °C; (i) R2NH2, iPr2NEt, DMSO, 120 °C; (j) NaH, di(1H-imidazol-1-yl)methanone, DMF, 0?75 °C; (k) SOCl2, cat. DMF,
CH2Cl2, 23 °C then R3R4NH, CH2Cl2, 23 °C; (l) 6-methoxypyridin-3-ylboronic acid, Pd(Ph3P)4, Na2CO3, dioxane, water, reflux.
Table 1
To examine the potential of this geometry we synthesized sev-
Comparison of the PDE5 potency and PDE6 and PDE11 selectivity of 1,3 southeastern
and southern pyridines to 1,4 southeastern and southern pyridines
eral prototype compounds in both the southeastern and southern
pyridine core ring systems. The syntheses of these rings systems
are illustrated in Scheme 1. Synthesis of 1,4 southeastern pyri-
OMe
OMe
OPr
dines (general structure 11) commenced with the chlorination
of dihydroxy pyridine 4 in neat POCl3 to yield 5. Displacement
of the 4-chloro group in 5 with various primary amines pro-
ceeded smoothly and in good yield to give 6. Saponification fol-
lowed by formation of the primary amide gave 8 in nearly
quantitative yield. Suzuki cross coupling between 8 and 6-meth-
oxypyridin-3-ylboronic acid yielded 9 in 65% yield. Treatment of
9 with CDI and sodium hydride provided the penultimate dione,
10, in excellent yield. Finally, chlorination of 10 with POCl3 pro-
vided the highly reactive intermediate chloropyrimidinone which
was immediately reacted with the requisite amines to give 11.
The synthesis of the southern pyridine derived isomers (16) pro-
ceeded along a similar synthetic route. We began from the known
intermediate 12 which was converted to the analogous amide by
the action of 7 N NH3. Treatment of this compound with primary
amines in DMSO at 120 °C proceeded in modest yield to provide
13. Treatment of amino amide 13 with CDI and sodium hydride
provided 14. Chlorination with SOCl2 followed by displacement
with amines afforded the aminopyrimidinones, 15. The synthesis
of 16 was completed via a Suzuki cross coupling (42% yield).
Table 1 summarizes the PDE5 potency and PDE6 and PDE11
selectivity and compares the characteristics of the 1,3 and 1,4
geometries in both the southeastern and southern pyridine cores.
The PDE5 potency of the 1,4 geometry was similar to what we
had determined for the 1,3 system. For instance, morpholines 1
(PDE5 IC50 = 0.07 nM) and 17 (PDE5 IC50 = 0.08 nM) were equipo-
tent against PDE5 as were southeastern cyclohexanols 2 (PDE5
IC50 = 0.05 nM) and 18 (PDE5 IC50 = 0.05 nM). For both piperazine
pairs (3 and 21 and 22 and 23) there was approximately a fivefold
loss in potency in the 1,4 geometry as compared to the 1,3 geom-
etry; however, both 21 and 23 possess nanomolar potency against
PDE5 (IC50 = 1.38 and 1.64 nM, respectively). We were further
encouraged by the suggestion from this early set of compounds
OPr
O
N
N
O
N
N
N
N
Y
X
Y
X
3R4RN
NR3R4
1,3SE: X = CH2, Y = N
1,3S : X = N, Y = CH2
1,4SE: X = CH2, Y = N
1,4S: X = N, Y = CH2
X
Core
–NR3R4
PDE5a
6x/11xb
H
N
1
1,3SE
0.07
158/4860
N
O
17
2
18
1,4SE
1,3SE
1,4SE
0.08
0.05
0.05
334/9050
200/1316
675/3950
H
N
19
1,3S
0.32
48/675
HO
HO
20
3
21
1,4S
1,3SE
1,4SE
0.10
0.20
1.38
1020/3830
157/2463
181/>1450
N
22
23
1,3S
1,4S
0.35
1.64
245/1771
N
381/>1220
a
PDE IC50 (nM).
b
6x = PDE6 IC50/PDE5 IC50; 11x = PDE11 IC50/PDE5 IC50
.
that the 1,4 geometry might afford more selectivity, particularly
over PDE6, than the analogous 1,3 compound. For example, 20 is
significantly more selective than 19 (1020-fold vs 48-fold).7
Encouraged by these early results we designed and synthesized
a diverse library of compounds to rapidly establish the key features

6350
R. O. Hughes et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6348–6352
(11) as its synthesis allowed for the installation of the solvent re-
gion in the last step. The results for 115 compounds are summa-
rized graphically in Figure 3. As shown in panel (a) of Figure 3,
82% of these compounds possessed PDE5 IC50s <1 nM. Further,
98% of the compounds synthesized demonstrated both PDE6 and
PDE11 selectivities greater than and 100-fold. Figure 4 shows crys-
tallographic data8 for both 1,3 (1) and 1,4 compound compounds
bound to PDE5. In this instance, the two relatively flexible side-
chains (ethyl morpholine and ethyl isopropoxyl) occupy a similar
area of space. This observation explains the similar PDE5 potency
findings between the two series. Moreover, this observation gave
us the confidence to forgo a wide ranging potency optimization
campaign for the 1,4 series as this would most likely only duplicate
the efforts and results obtained during the optimization campaign
for the 1,3 series. Instead we chose to focus our attention on incor-
porating the optimal groups identified during the optimization of
the 1,3 system into the 1,4 series.
Figure 3, panel (b) illustrates the trend relating in vitro meta-
bolic stability (human liver microsomes, percent remaining after
one hour of incubation) to calculated lipophilicity (clogD). The
probability of a compound displaying favorable metabolic stability
increased steadily with reduced clogD. Specifically, the probability
is 90% (clogD <1), 70% (1 < clogD < 2) and 35% (clogD >2). In order
to increase the probability of finding compounds with an excellent
potency, selectivity and metabolic stability profile, we sought core
structural modifications which would retain high potency at lower
lipophilicity. Accordingly we considered pyridazine ring systems
such as 31 (see Scheme 2).
Synthesis of the pyridazines (general structure 31) is summa-
rized in Scheme 2 and initiated with known pyridazine-3,4,6-triol
(24). Chlorination with POCl3 give the relatively stable tri-chloro
compound, 25, from which the desired was chlorine was dis-
placed by the action of primary amines in ethanol. As the key
step, regioselective palladium-mediated carbonylation of 26 pro-
vided methyl ester 27 in 85% yield. Direct conversion to the pri-
mary amide, 28, was brought about by treatment with 7 N NH3 in
Figure 3. (a) Summarizes the selectivity and potency data of broad set of
compounds examining the solvent region. Green boxes denote PDE5 IC50
<0.1 nM; yellow boxes 0.1 nM < PDE5 IC50 < 1 nM; and blue boxes 1.0 nM < PDE5
IC50. (b) Illustrates the relationship between calculated logD and human liver
microsomal stability. PDE11-fold and PDE6-fold refer to the ratio: PDE11 IC50/PDE5
IC50 and PDE6 IC50/PDE5 IC50, respectively.
R1
R1
R1
R2HN
Cl
b
e
g
N
N
N
Cl
26
N
24: R1 = OH
25: R1 = Cl
a
c
R2
R2HN
R3
Cl
O
N
Cl
N
HN
N
N
N
O
O
27: R3 = OMe
28: R3 = NH2
d
29
f
R2
OMe
R2
O
N
Cl
O
N
N
N
N
N
N
N
N
NR3R4
NR3R4
30
31
Figure 4. Cystallographic data for 1,3 analog 1 (yellow), bearing the morpholino-
ethylamino side chain, and a 1,4 analog (orange),9 bearing the isopropoxyethyl
amino side chain, bound to PDE5.
Scheme 2. Reagents and conditions: (a) POCl3, 100 °C; (b) R2NH2, ethanol, 0 °C; (c)
CO, Pd(dppf)2, methanol, DMF, 80 °C; (d) 7 N NH3, MeOH, 0?23 °C; (e) NaH, di(1H-
imidazol-1-yl)methanone, DMF, 0?75 °C; (f) oxalyl chloride, cat. DMF, dichloro-
methane, 0?23 °C then R3R4NH, CH2Cl2, 0?23 °C; (g) 6-methoxypyridin-3-ylbo-
ronic acid, Pd(Ph3P)4, Na2CO3, dioxane, water, reflux.
of the 1,4 geometry in the solvent region. We choose to conduct
this evaluation utilizing the southeastern pyridine ring system

R. O. Hughes et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6348–6352
6351
methanol. Cyclization of 28 with CDI gave 29. The synthesis was
completed in a similar manner as the southeastern and southern
pyridine isomers. Specifically, chlorination of 29 with thionyl
chloride followed by immediate treatment of the highly reactive
chloropyrimidine with amines gave 30 which was converted to
the final, desired product (31) via Suzuki cross-coupling.
Table 2 summarizes the PDE5 potency and PDE6 and PDE11
selectivity for a series of pyridazine-derived compounds. As antici-
pated from our initial scan of the solvent region (Fig. 3), a wide vari-
ety of substitution patterns were well tolerated in terms of both
PDE5 potency and PDE6 and PDE11 selectivity. For instance, basic
amines 32 (PDE5 IC50 = 0.09 nM; PDE6 and PDE11 >500-fold) and
33 (PDE5 IC50 = 1.31 nM; PDE6 and PDE11 >500-fold) and neutral
alcohols such as 34 (PDE5 IC50 = 0.22 nM; PDE6 and PDE11 >250-
fold) and 35 (PDE5 IC50 = 0.28nM; PDE6 and PDE11 >200-fold) dis-
played an excellent in vitro profile. Interestingly, as carboxylic acids
were not well-tolerated in the 1,3 geometry, 36 was observed to
have an excellent potency and selectivity profile. Interestingly,
the increase in polarity of pyridazine (relative to the pyridine iso-
mers) does not result in a loss of potency. Examination of the
pair-matched set of 20 solvent groups, comparing the pyridazine
core to the southeast pyridine core showed that the ligand effi-
ciency10 was similar (0.42 for the pyridazines and 0.41 for the
southeast pyridine) but the lipophilic ligand efficiency11 increased
significantly (7.2 for the pyridazines and 6.5 for the southeast pyr-
idine). This increase in lipophilic efficiency improved our ability to
design potent, selective and metabolically stable molecules.
Analogs 37–45 were designed to probe the contributions to po-
tency, selectivity and PK of the alkoxy substituent (see Table 2).
Both less lipophilic groups, such as ethyl ethoxy, and metaboli-
cally-blocked groups, such as ethyl trifluoroethoxy, retained excel-
lent potency and selectivity. Indeed, the ethyl trifluoroethoxy
group afforded a significant improvement in PDE6 and PDE11
selectivity. The ethyl ethoxy group was somewhat less active than
the ethyl propyloxy.
Table 3 summarizes the in vitro and in vivo PK properties of
three analogs from the cyclohexanol series compared to the 1,3
compound 2. All four compounds possessed excellent in vitro met-
abolic stability as judged by incubation with human liver micro-
somes. Furthermore, 40 and 42 demonstrated low clearance
(<10 mL/min/kg), a low volume of distribution (1–2 L/kg) and high
bioavailability (85–100%) in the these studies. Interestingly, the tri-
fluoroethyl derivative, 41, possessed a significantly higher clear-
ance (36.5 mL/min/kg) and volume of distribution (4.8 L/kg).
Comparison of the unbound clearance of 40 to 2 highlights the dra-
matic increase in intrinsic metabolic stability of 40. Furthermore,
40 and 42 possessed improved solubility profiles as compared to 2.
Based on its favorable potency, selectivity and pharmacokinetic
profile, compound 40 was extensively profiled. As with compounds
such as 2 and 3, from the 1,3 series, 40 demonstrated excellent
selectivity against the other members of the PDE family as well
Table 2
Summary of PDE5 potency and PDE6 and PDE11 selectivity for
pyradiazines
a series of 1,4
R
OM
O
N
N
N
N
N
NR3R4
X
R
–NR3R4
PDE5a
0.09
6x/11xb
H
N
32
573/6820
N
O
NH
as against a wide panel of targets.12 At 3
lM, 40 did not signifi-
33
34
35
1.31
0.22
0.28
576/1530
290/240
194/240
cantly inhibit CYP2C9 (9%), CYP3A4 (23%) nor CYP2D6 (5%). In
our pharmacodynamic model in the spontaneously hypertensive
rat, 40 demonstrated robust blood pressure lowering (systolic BP
HN
HO
H
N
Me
Me
O
D
= ꢀ20–30 mmHg) for >24 h following a single dose of 20 mpk.
N
Additional studies indicated, as previously noted, that efficacy
was maintained when trough, free plasma concentrations ex-
ceeded 10xPDE5 IC50. Taking this data together with the preclinical
PK profile we predicted a human PK profile supportive of once-a-
day dosing with a low dose of less than 5 mg. Additional data on
40 will be reported in due course.
HO
H
N
HO
O
36
37
38
0.05
1.30
0.64
139/250
124/834
818/>311
O
O
Table 3
CF3
N
Summary of pharmacokinetic properties of 2, 40, 41 and 42
N
HO
HO
Property
2
40
41
42
39
40
2.43
0.02
98/286
O
O
O
Me
Me
clogD
1.3
21
84
5.5
392
1.35
96
1.4
50
0.79
>100
72
2.4
19.2
0.6
4.8
12.5
85
1.6
0.3
0.47
34
0.23
>100
63
9.4
ND
1.3
ND
ND
100
ND
ND
Solubilitya
HLMb
108/741
100
36.5
ND
4.8
ND
ND
73
Rat Clc
Rat Clu
Rat Vdd
Rat Vdu
Rat fue
Rat% Ff
Dog Clc
Dog Vdd
H
N
CF3
41
0.04
3620/11,400
42
43
0.36
0.44
125/506
296/277
O
O
O
Me
5.5
3.5
ND
ND
Me
a
b
c
O
H
N
Solubility (
l
M) at pH 6.5.
CF3
Me
Me
44
45
0.38
1.47
2200/4170
119/199
% remaining after 1 h in human liver microsomes.
Clearance in mL/min/kg; 2 mpk (n = 3) vehicle: 70% PEG400/20% 0.05 M citrate
N
Me
buffer/10% ethanol, pH 5.
d
Volume of distribution in L/kg.
Fraction unbound.
2 mpk (n = 3) vehicle: 0.5% methylcellulose/0.1% Tween 80 in 50 mM citric acid,
O
e
a
f
PDE IC50 (nM).
6x = PDE6 IC50/PDE5 IC50; 11x = PDE11 IC50/PDE5 IC50
b
.
pH 5.

6352
R. O. Hughes et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6348–6352
Table 4
PDE6 and PDE11 selectivity data for this set of compounds is
summarized in Table 4. As observed with compound 36, these com-
pounds examined possessed sub-nanomolar PDE5 potency and an
excellent selectivity profile. Interestingly, racemic stereoisomers
49 and 50 displayed somewhat disparate potency and selectivity
profiles. The trans-isomer, 50, was an order of magnitude less potent
(PDE5 IC50 = 0.27 nM) and less PDE6 selective but more PDE11
selective than the cis-isomer. Unfortunately, evaluation of this ser-
ies of compounds in vivo suggested high, non-hepatic clearance.
The rat PK for 48 is representative of the series: clear-
ance = 195 mL/min/kg and %F = 17, following a 2 mpk iv and po
dose. Efforts to improve the PK profile were not successful and the
acidic sub-series was de-emphasized.
Summary of the PDE5 potency and PDE6 and PDE11 selectivity for a series of acidic
analogs
OMe
OPr
O
N
N
N
N
N
NR3R4
X
–NR3R4
PDE5a
0.13
6x/11xb
110/76
O
H
N
Me
46
HO
In summary, we have described the design and synthesis of a
novel series of PDE5 inhibitors which exploited an alternate pro-
jection into the solvent region. Compound 40 was rapidly identi-
fied as an attractive lead molecule and was extensively profiled.
O
H
N
Me
47
48
0.05
0.01
145/129
HO
Me
References and notes
HN
O
172/2090
1. Rashid, A. Clin. Cornerstone 2005, 7, 47.
2. Sandner, P.; Huetter, J.; Tinel, H.; Ziegelbauer, K.; Bischoff, E. Int. J. Impot. Res.
2007, 19, 533.
HO
3. Hughes, R. O.; Walker, J. K.; Cubbage, J. W.; Fobian, Y. M.; Rogier, D. J.; Heasley,
S. E.; Blevis-Bal, R. M.; Benson, A. G.; Owen, D. R.; Jacobsen, E. J.; Freskos, J. N.;
Molyneaux, J. M.; Brown, D. L.; Stallings, W. C.; Acker, B. A.; Maddux, T. M.;
Tollefson, M. B.; Williams, J. M.; Moon, J. B.; Mischke, B. V.; Rumsey, J. M.;
Zheng, Y.; MacInnes, A.; Bond, B. R.; Yu, Y. Bioorg. Med. Chem. Lett. 2009, 19,
4092.
4. Hughes, R. O.; Walker, J. K.; Joseph, R. D.; Heasley, S. E.; Blevis-Bal, R. M.;
Benson, A. G.; Jacobsen, E. J.; Cubbage, J. W.; Fobian, Y. M.; Owen, D. R.; Freskos,
J. N.; Molyneaux, J. M.; Brown, D. L.; Acker, B. A.; Maddux, T. M.; Tollefson, M.
B.; Moon, J. B.; Mischke, B. V.; Rumsey, J. M.; Zheng, Y.; MacInnes, A.; Bond, B.
R.; Yu, Y. Bioorg. Med. Chem. Lett. 2009, 19, 5209.
5. Hughes, R. O.; Rogier, D. J.; Jacobsen, E. J.; Walker, J. K.; MacInnes, A.; Bond, B.
R.; Zhang, L. L.; Yu, Y.; Zheng, Y.; Rumsey, J. M.; Walgren, J. L.; Curtiss, S. W.;
Fobian, Y. M.; Heasley, S. E.; Cubbage, J. W.; Moon, J. B.; Brown, D. L.; Acker, B.
A.; Maddux, T. M.; Tollefson, M. B.; Mischke, B. V.; Owen, D. R.; Freskos, J. N.;
Molyneaux, J. M.; Benson, A. G.; Blevis-Bal, R. M. J. Med. Chem. 2010, 53, 2656.
6. Southern and Southeastern pyridine refer to the location of the Nitrogen in the
right-hand ring (as drawn) system. The propoxy group is on the ‘northern’ side
of the ring system.
NH
49
50
0.27
0.02
47/1390
110/296
COOH
NH
COOH
O
NH
N
51
52
0.02
0.04
246/541
HO
254/1060
HOOC
O
N
53
0.01
119/532
HO
7. Presently, we do not have a compelling structure-based rationale for this
finding.
8. PDB accession codes: 3TGE and 3TGG.
N
9. Data
for
4-[(2-isopropoxyethyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-
propoxyethyl)pyrido[4,3-d]pyrimidin-2(1H)-one: PDE5 IC50 = 0.1 nM; PDE6/
PDE5 = 450-fold; PDE11/PDE5 = 9560-fold.
10. Hopkins, L. A.; Groome, C. R.; Alex, A. Drug Discovery Today 2004, 9, 430.
11. Ryckmans, T.; Edwards, M. P.; Horne, V. A.; Correia, A. M.; Owen, D. R.;
Thompson, L. R.; Tran, I.; Tutt, M. F.; Young, T. Bioorg. Med. Chem. Lett. 2009, 19,
4406.
12. For the PDE family we determined: PDE1A, PDE1B, PDE1C, PDE2, PDE3A,
PDE3B, PDE4A, PDE4B, PDE4C, PDE7A, PDE7B, PDE8A, PDE8B, PDE9 and PDE10
IC50 >2000 nM. Screening in the CEREP broad screen of >50 off-targets at
10 mM revealed only two weak hits: adenosine A1 IC50 = 440 nM and
acetylcholinesterase IC50 = 5600 nM.
54
55
0.06
0.10
162/297
OH
O
N
143/1330
HOOC
N
a
PDE IC50 (nM).
b
6x = PDE6 IC50/PDE5 IC50; 11x = PDE11 IC50/PDE5 IC50
.
Intrigued by the potency and selectivity profile of 36 we evalu-
ated additional carboxylic acid derivatives. The PDE5 potency and