Discovery of thiadiazoles as a novel structural class of potent and selective PDE7 inhibitors. Part 1: Design, synthesis and structure-activity relationship studies

Article abstract of DOI:10.1016/j.bmcl.2004.07.008

The synthesis and SAR studies of a series of structurally novel small molecule inhibitors of PDE7 are discussed. The best compounds from the series displayed low nanomolar inhibitory activity and are selective versus PDE4.

Full text of DOI:10.1016/j.bmcl.2004.07.008

Bioorganic & Medicinal Chemistry Letters 14 (2004) 4607–4613
Discovery of thiadiazoles as a novel structural class of potent
and selective PDE7 inhibitors. Part 1: Design, synthesis
and structure–activity relationship studies
a
a
a
Fabrice Vergne,a, Patrick Bernardelli, Edwige Lorthiois, Nga Pham,
*
Emmanuelle Proust,a Chrystelle Oliveira,a Abdel-Kader Mafroud,a Frederique Royer,a
Roger Wrigglesworth,a Jennifer K. Schellhaas,b Mark R. Barvian,b Franc¸ois Moreau,a
Moulay Idrissi,a Anita Tertre,a Bernadette Bertin,a Magali Coupe,a Patrick Bernaa and
Patricia Soulardc
aPfizer Global Research and Development, 3-9 Rue de la loge 94265 Fresnes, France
bPfizer Global Research and Development, Ann Arbor laboratories, 2800 Plymouth Road, MI 48105, USA
cPfizer Discovery Technology Center, 620 Memorial Drive, Cambridge, MA 02139, USA
Received 23 January 2004; revised 18 June 2004; accepted 2 July 2004
Available online 29 July 2004
Abstract—The synthesis and SAR studies of a series of structurally novel small molecule inhibitors of PDE7 are discussed. The best
compounds from the series displayed low nanomolar inhibitory activity and are selective versus PDE4.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
lated diseases,3 CNS disorders,5 leukaemia,6 and fertility
disorders.7 Development of specific inhibitors8 repre-
sents one of the approaches to uncover the physiological
roles of PDE7. High throughput screening of the com-
pound collection resulted in the identification of the
1,3,4 thiadiazole 1 (Fig. 1) as a weak PDE7 inhibitor
with an IC50 of 1.5lM.
The family of phosphodiesterases (PDEÕs) regulate levels
of secondary messengers adenosine and guanosine 30,50-
cyclic monophosphates (cAMP and cGMP, respectively)
via hydrolysis to their corresponding inactive 50-mono-
phosphate nucleotides.1 Inhibition of cAMP-specific
PDE activity causes an increase in concentrations of
cAMP thereby activating protein kinases responsible
for various biological processes. At least 11 isoenzymes
of mammalian cyclic nucleotide phosphodiesterase have
been identified.2 Among them, PDE7 is a high affinity
cAMP-specific PDE (Km =200nM) with kinetic proper-
ties distinct from those of PDE4 (PDE7 Km is about 10-
fold lower than PDE4). Based on the functional role of
PDE7 in T-cell activation3 and the corresponding levels
and localization of the mRNA, PDE7 inhibitors might
be useful in the treatment of airway diseases,4 T-cell re-
This article describes our preliminary efforts towards op-
timizing the enzymatic inhibitory activity and the selec-
tivity profile of these compounds versus other PDEs
(especially PDE4, which is also a cAMP-specific PDE).
The SAR studies on the thiadiazole template led to the
Keywords: PDE7; Phosphodiesterase; cAMP.
*
Corresponding author at present address: Aventis Pharma, 13 Quai
Jules Guesde, 94400 Vitry-sur-Seine, France. Tel.: +33-158932962;
fax: +33-158938014; e-mail: fabrice.vergne@aventis.com
Figure 1. Schematic representation of 1.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.07.008

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F. Vergne et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4607–4613
Figure 2. Schematic representation of the inhibitors designed from 1.
discovery of several potent and selective PDE7 inhibi-
tors exemplified by 16, 56 and 59 (Fig. 2).
ported by Molina et al.10 Substituted hydrazine A was
reacted with carbon disulfide and methyl iodide in pres-
ence of potassium hydroxide to form the hydrazine car-
bodithioate B. The key intermediate 1,3,4-thiadiazolium
perchlorate D was then generated after acylation of B
followed by intramolecular cyclization in presence of
acetic anhydride and perchloric acid D is then reacted
with a suitable amine to yield the targeted thiadiazole
L. Route B: thiadiazole L is prepared from reaction of
isothiocyanate (R1NCS) with substituted hydrazines A
to give E, followed by successive condensation of the hy-
drazine carbothioamide E with aldehyde (R2CHO) and
2. Chemistry
The thiadiazole derivatives were prepared according to
well reported routes9 as described in Scheme 1.
Four synthetic methods were explored to bring the
appropriate chemical diversity at R1, R2 and R3. Route
A: the reaction conditions for this method were first re-
Scheme 1. Reagents and conditions:9 route A:10 (a) CS2, MeI, KOH, EtOH, 0–15°C; (b) R2COCl, toluene, reflux; (c) Ac2O, HClO4, Et2O, ꢀ5 to
5°C; (d) R1NH2, alcohol (EtOH), Et3 N, 40–80°C; route B:11 (e) R1NCS, EtOH, ꢀ5 to 15°C; (f) R2CHO, MeOH, 50–90°C; (g) FeCl3, alcohol
(EtOH), 20–110°C; route C:12 (h) R2COOH, POCl3, 1,4-dioxane, reflux; route D:12 (i) R1NCS, EtOH, ꢀ5 to 15°C; (j) R2COOH, POCl3, 1,4-dioxane,
reflux; (k) MeX, aprotic solvent, rt to 80°C.

F. Vergne et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4607–4613
4609
by oxidative cyclization of the resulting SchiffÕs base F in
presence of iron(III) chloride according to Noto et al.11
Route C: is a one pot cyclization procedure performed
by reaction of substituted (R3) hydrazine carbothio-
amide E with carboxylic acid (R2COOH) in presence
of dehydrating agents12 (e.g., POCl3). Route D: reaction
of hydrazine H with isothiocyanate (R1NCS) generated
the corresponding intermediate I, which was reacted
with carboxylic acid and in situ thermally cyclized in
presence of dehydrating agent to afford K. The last step
is a N-alkylation with electrophiles12 (alkyl triflate,
iodide or bromide) to give the desired thiadiazoles L.
Replacement of the cyclohexyl structural part in 1 by
carbocycles (2–5) was devised to define the effect of the
ring size and shape on activity and selectivity.
As illustrated by compounds 1, 4 and 5, six or eight-
membered ring systems allows to maintain a micromolar
activity associated with a high selectivity versus PDE4.
The analogue 2 with a smaller ring was not as selective.
The incorporation of some heteroatoms into or onto
carbocycles (6–8), which could be beneficial for solubil-
ity was shown to be detrimental to the enzymatic activ-
ity. When the cyclohexyl side chain was replaced by
linear (and branched) alkyl chains (9–12), a loss in
potency was observed.
3. Biological results13 and discussion
The phenyl analogue 13 showed a slight decrease of
activity compared to 1. As a final outcome of these pre-
liminary SAR studies, these chemical modifications sug-
gested that hydrophobic steric bulk (R1) was favourable
for activity and selectivity versus PDE4.
The different and complementary chemical approaches
(Scheme 1) allowed us to undertake a rapid survey of
the molecule to determine the best path for further
SAR studies around the R groups. Starting from 1,
various chemical modifications of the R3 group while
maintaining R2 as para-chlorophenyl group and R1 as
cyclohexyl group, did not lead to a significant improve-
ment in terms of inhibitory activity compared to 1 (data
not shown). Then, as a first approach, we decided to
keep unchanged the R3 substitution by maintaining
the methyl group. We focused on determining the
SAR of the R1 and R2 groups more thoroughly.
We next focused our attention on introducing ionizable
and polar functions on the phenyl ring 13 with the objec-
tive to evaluate the critical determinants for activity,
selectivity and solubility. Table 2 illustrates the inhibi-
tory activity of some representative analogues prepared
in this sub-series.
None of the monosubstituted neutral derivatives (14, 15,
20–23, 25) provided any significant enhancement com-
pared to the reference derivatives (1 or 13), resulting in
a flat SAR. The most dramatic improvement in inhibi-
tory activity resulted from substitution at the 3-position
with a carboxylic acid type function as illustrated by 16,
17 and 18.
Using a parallel synthesis approach, a large number of
different R1 groups were introduced (route A) and eval-
uated. Table 1 lists the structures and the inhibitory
activities of selected analogs from this study.
The soluble meta-benzoic acid derivative 16 with an IC50
of 140nM exhibited a 10-fold increase in activity com-
pared to the hit 1. In addition, 16 was found to be more
than 150-fold selective versus PDE4 and at least 50-fold
versus the other PDEs. Among the two carboxylic acid
bioisosteres prepared (17 and 18), only 18 was more po-
tent (IC50 =80nM) compared to 16. However, it is worth
noting that both isosteric replacements were not as selec-
tive as than the corresponding carboxylic acid 16, espe-
cially versus PDE4, PDE1 and PDE3. These results
suggest that pKa could have an impact on activity and
selectivity. In addition, compound 24 (33-fold less active
compared to 16) revealed the importance of the relative
position of the COOH function with respect to the phe-
nyl ring and, as illustrated by 19, elongation of the chain
was detrimental to the inhibitory activity (over 15-fold
loss in potency). Substitution of the meta-benzoic acid
derivative 16 seemed to be tolerated at the 4-position
(29–30) but in contrast, as illustrated by 26–28, substitu-
tion at the 2-position decreased the inhibitory activity,
confirming the results observed with 14 versus 15 and
23.
Table 1. In vitro dataa for compounds 1 and 2–13
Compda R1
PDE7A1 PDE4D3
IC50, lMb IC50, lMb
1
–Cyclohexyl
–Cyclobutyl
1.50
4.80
3.08
1.05
1.65
5.90
5.90
57.00
6.30
81.50
2
3
–Cyclopentyl
–Bicyclo[2.2.1]hept-2-yl
–Cyclooctyl
4
>101
>101
79.00
5
6
–1-Azabicyclo[2.2.1]hept-3-yl
–trans-4-Aminocyclohexyl
7
>101
>101
>101
8
–1-(Hydroxymethyl)cyclopentyl 4.00
9
–1-Ethylpropyl
–Isopropyl
–Propyl
5.60
3.90
7.70
1.90
2.95
10
11
12
13
17.00
26.00
37.00
38.00
–2-Hydroxy-1,1-dimethylethyl
–Phenyl
In conclusion to these studies around R1, the cyclohexyl
and the meta-benzoic group were the preferred struc-
tural features identified to bring some inhibitory
activity.
a All the compounds have been prepared by route A.
b Measured against the human full length enzyme produced in
baculovirus infected sf9 cells. Values are means of three experi-
ments.

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F. Vergne et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4607–4613
Table 2. In vitro data for compounds 14–30
Compdsa
R4
PDE7A1
IC50, lMb
PDE4D3
IC50, lMb
PDE1
IC50, lMc
PDE3A3
IC50, lMb
PDE5
IC50, lMd
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2-OH
3-OH
3-COOH
5.3
1.8
>101
>101
21.33
5.63
>101
9.81
>101
6.13
7.47
>101
10.94
7.27
0.14
0.44
0.080
2.13
5.7
16.38
3.56
3.34
3-[5-Hydroxy-1,2,4-oxadiazol-3-yl]
3-[2H-tetrazol-5-yl]
3-CH2COOH
3-CN
1.89
1.71
7.56
7.00
4.26
23.00
36.33
44.50
>101
13
40.34
>101
7.83
8.57
47.21
2.65
20.16
>101
>101
>101
>101
40.35
101
3-CONH2
3-F
1.63
6.6
>101
>101
28.93
85.68
28.84
14.06
9.28
>101
101
4-OH
4-COOH
4-F
1.7
4.60
2.2
>101
>101
58.25
20.5
30.68
>101
49.42
20.54
9.83
2-OH, 5-COOH
2-Me, 5-COOH
2-OH, 3-COOH
3-COOH, 4-F
3-COOH, 4-OH
1.31
1.37
0.26
0.16
0.15
18.77
23.60
5.18
14.2
39.66
7.05
21.58
5.23
16.98
5.58
17.88
3.97
a Compounds 3 and 29–44 prepared by route A.
b Measured against the human full length enzyme produced in baculovirus infected sf9 cells. Values are means of three experiments.
c Measured against the human full length enzyme partially purified from THP-1 cell pellets. Values are means of three experiments.
d Measured against the human full length enzyme partially purified from MCF-7 cell pellets. Values are means of three experiments.
We next examined the SAR of the R2 chemical part.
Table 3 summarizes a broad survey around the impact
of phenyl substitution (R5) on activity and selectivity
versus PDE4. Preliminary modification of the relative
position of the OH, COOMe or Cl group from ortho
to meta or para position resulted in a clear increase in
inhibitory activity as exemplified by comparison of 31–
33 with 1, 34–36 or 41–42. Consequently, the 3 and 4-
position were targeted for more detailed chemical inves-
tigations. Interestingly, a more pronounced effect was
demonstrated with neutral hydrogen bond donor
(HBD) or hydrogen bond acceptor (HBA) groups as
illustrated by 34–35 compared to 36 or by 41–42 com-
pared to 1, 45 and 47.
and by a N-substitution of the sulfonamide function
with an ethyl chain (54). These modifications resulted
in nearly 70-fold increase in activity compared to 1, with
more than 260-fold selectivity versus PDE4.
The best balance between activity and solubility within
the amide series was found with compounds 56
(IC50 =30nM, solubility=17lg/mL at pH7.4) and 57
(IC50 =65nM, solubility=83lg/mL at pH7.4) prepared
by a coupling reaction between 45 and the correspond-
ing primary amines.
The fact that the secondary amide 57 is more potent
than the corresponding N-methylated product 55 sup-
ports the hypothesis of the important role of HBD func-
tions for activity. Focusing on the 4-CONH2 derivatives,
we varied the nature of functional groups at the 3-posi-
tion as shown in Table 3 by compounds 49–52. Incorpo-
ration of a methyl or a methoxy group at the 3-position
(49 and 50, respectively) did not allow to improve activ-
ity compared to the nonsubstituted compound 44. In
contrast, introduction of the 3-OH (51) or 3-NH2 (52)
maintained the level of activity in the same range as
for the reference derivative 44.
Consequently, we undertook an analysis of the impor-
tance of these properties on activity and selectivity by
the preparation of some compounds combining both
HBD and HBAproperties ( Table 3).
As expected, substitutions with some neutral HBD/HBA
groups such as amide (38, 44, 48) or a combination of
OH and OMe functions (40) caused a dramatic improve-
ment in activity with compounds displaying IC50 values
in the 60nM range. The primary sulfonamides (37, 43)
were found less potent compared to the corresponding
amide analogues (38, 44). Based on the fact that sulfon-
amides and amides allow wide chemical variations, sev-
eral analogues were prepared to improve drug-like
properties. The sulfonamide 37 was optimized by intro-
duction of a chloro-substituent at the 4-position (53)
These latter results suggest a nearly planar ring system
as the favourable conformation for PDE7 affinity, due
to an intramolecular hydrogen bond interaction between
the lone electron pair of the oxygen atom from the car-
bonyl function (4-position) and the available hydrogen
atom of the donor group at the 3-position.

F. Vergne et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4607–4613
Table 3. In vitro data for compounds 31–57
4611
Compds
Route
R5
PDE7A1 IC50, lMa
PDE4D3 IC50, lMa
31
32
33
34
35
36
37
38
39
40
41
42
1
D
D
B
2-OH
2-COOMe
6.40
7.50
1.30
0.29
0.14
0.70
0.20
0.09
0.87
0.061
0.24
0.23
1.5
71.00
30.00
40.00
22.17
19.00
2-Cl
3-OH
D
D
B
3-COOMe
3-Cl
>101
C
3-SO2 NH2
3-CONH2
3-COOH
15.05
19.25
22.25
11.88
12.23
95.5
D
D
D
D
D
D
D
D
D
B
3-OH, 4-OMe, 5-OH
4-OH
4-COOMe
4-Cl
4-SO2NH2
57.00
10.97
15.3
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
0.15
0.061
0.55
0.13
0.56
0.068
0.93
0.47
0.12
0.083
0.069
0.022
0.47
0.030
0.065
4-CONH2
4-COOH
32.25
25
4-SO2Me
4-NH2
C
25.75
34.25
44.66
C
4-NHCOCH3
3-Me, 4-CONH2
3-OMe, 4-CONH2
3-OH, 4-CONH2
3-NH2, 4-CONH2
3-SO2NH2, 4-Cl
3-SO2NHEt, 4-Cl
4-CON(Me)CH2CH2N(CH3)2
4-CONHCH2CH2-N-morpholinyl
4-CONHCH2CH2N(CH3)2
D
D
D
D
D
D
D
D
D
>101
19.33
26.00
5.90
5.84
>101
8.77
33.33
a Measured against the human full length enzyme produced in baculovirus infected sf9 cells. Values are means of three experiments.
Table 4. In vitro data for compounds 52 and 58–59
Based on this hypothesis and in order to improve activ-
ity, further changes were devised aimed at designing a
rigid bioisostere of the amino-amide system able to
mimic the same type of HBD/HBAproperties. The most
evident option was to prepare 4-aminoquinazoline
derivatives, which are, interestingly, structural ana-
logues of the adenine part of cAMP. As expected, two
of these analogues presented in Table 4 led to highly po-
tent inhibitors illustrated by compounds 58 and 59. The
4-amino-2-methylquinazoline derivative 59 displayed an
IC50 of 3.9nM on the PDE7 enzyme and exhibited a
very high selectivity versus PDE4.
Compds
Ar
PDE7A1
IC50, lMa
PDE4D3
IC50, lMa
52
0.083
26.00
The quinazoline derivatives 58 and 59 have been pre-
pared by a modified route shown in Scheme 2.
58
59
0.027
>101
92.33
4. Conclusion
In conclusion, a dramatic improvement in activity and
selectivity was achieved from the micromolar hit com-
pound 1 by modification of R1 and R2 chemical parts.
We have highlighted a structurally novel series of
PDE7 inhibitors (Fig. 2) displaying low nanomolar
0.0039
a Measured against the human full length enzyme produced in bacu-
lovirus infected sf9 cells. Values are means of three experiments.

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F. Vergne et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4607–4613
Scheme 2. Reagents and conditions: (a) RCONH2, (R@Me or H), 1-methyl-2-pyrrolidinone, 200°C; (b) methyl-1-methylhydrazine carbodithioate,
DMF, TOTU, 0°C; (c) TMSOTf, toluene, <40°C; (d) cyclohexylamine, EtOH, reflux; (e) SOCl2, toluene; (f) NH3, 1,4-dioxane, D.
Physiol. Lung Cell. Mol. Physiol. 2003, 284, L279–
L289.
inhibitory activity and exhibiting high selectivity over
PDE4. The findings from this study will be useful for
further optimization of these newly discovered chemical
leads, which will be the subject of additional reports in
due course.
5. (a) Perez-Torres, S.; Cortes, R.; Tolnay, M.; Probst, A.;
Palacios, J. M.; Mengod, G. Exp. Neurol. 2003, 182,
322–334; (b) Miro, X.; Perez-Torres, S.; Palacios, J. M.;
Puigdomenech, P.; Mengod, G. Synapse 2001, 40,
201–214; (c) Sasaki, T.; Kotera, J.; Omori, K. Biochem.
J. 2002, 361, 211–220.
Acknowledgements
6. Lee, R.; Wolda, S.; Moon, E.; Esselstyn, J.; Hertel, C.;
Lerner, A. Cell. Signal. 2002, 14, 277–284.
We thank the scientists from the Analytical Support
Group for their help in compound characterization and
Professor Anthony G. M. Barrett for helpful discussions
regarding the thiadiazole chemistry. We also thank the
Evotec OAI scientists for their assistance in this project.
7. (a) Kotera, J. PDE7- news and views, William Harvey
Research Conferences, Porto, Portugal, Dec 5–7, 2001; (b)
Kluxen, F. W. PCT int. Appl. WO 0183772 A1, 2001.
8. (a) Barnes, M. J.; Cooper, N.; Davenport, R. J.; Dyke, H.
J.; Galleway, F. P.; Galvin, F. C. A.; Gowers, L.;
Haughan, A. F.; Lowe, C.; Meissner, J. W. G.; Montana,
J. G.; Morgan, T.; Picken, L. C.; Watson, R. Bioorg. Med.
Chem. Lett. 2001, 11, 1081–1083; (b) Castro, A.; Abasolo,
M. I.; Gil, C.; Segarra, V.; Martinez, A. Eur. J. Med.
Chem. 2001, 36, 333–338; (c) Martinez, A.; Castro, A.; Gil,
C.; Miralpeix, M.; Segarra, V.; Domenech, T.; Beleta, J.;
Palacios, J. M.; Ryder, H.; Miro, X.; Bonet, C.; Casacu-
berta, J. M.; Azorin, F.; Pina, B.; Puigdomenec, P. J. Med.
Chem. 2000, 43, 683–689; (d) Pittz, W. J.; Vaccaro, W.;
Huynh, T.; Leftheris, K.; Roberge, J. Y.; Barbosa, J.;
Guo, J.; Brown, B.; Watson, A.; Donaldson, K.; Starling,
G. C.; Kiener, P. A.; Poss, M. A.; Dodd, J. H.; Barrish
J. C. Bioorg. Med. Chem. Lett. 2004, 14, 2955–2958.
9. Vergne, F.; Ducrot, P.; Andrianjara, C.; Bernardelli, P.;
Lorthiois, E. PCT int. Appl. WO 0228847 A1, 2002.
10. (a) Molina, P.; Tarraga, A.; Espinosa, A. Synthesis, 1988,
690–693; (b) Molina, P.; Tarraga, A.; Espinosa, A.
Heterocycles 1989, 29, 2301–2316.
References and notes
1. (a) Beavo, J. A. Physiol. Rev. 1995, 75, 725–748; (b)
Francis, S. H.; Turko, I. V.; Corbin, J. D. Prog. Nucleic
Acid Res. Mol. Biol. 2001, 65, 1–52; (c) Conti, M. In
Principles of Molecular Regulation; Conn, P. M., Means,
A. R., Eds.; Humana, 2000, pp 261–275; (d) Soderling, S.
H.; Beavo, J. A. Curr. Opin. Cell Biol. 2000, 12, 174–179.
2. (a) Soderling, S. H.; Bayuga, S. J.; Beavo, J. A. J. Biol.
Chem. 1998, 273, 15553–15558; (b) Conti, M.; Jin, S. L. C.
Prog. Nucleic Acid Res. Mol. Biol. 1999, 63, 1–38; (c)
Essayan, D. M. J. Allergy Clin. Immunol. 2001, 108,
671–680.
3. (a) Li, L.; Yee, C.; Beavo, J. A. Science 1999, 283,
848–851; (b) Nakata, A.; Ogawa, T.; Sasaki, T.; Koyama,
N.; Wada, K.; Kotera, J.; Kikkawa, H.; Omori, K.;
Kaminuma, O. Clin. Exp. Immunol. 2002, 128, 460–466.
4. Smith, S. J.; Brookes-Fazakerley, S.; Donnelly, L. E.;
Barnes, P. J.; Barnette, M. S.; Giembycz, M. A. Am. J.
11. (a) Noto, R.; Lo Meo, P.; Gruttadauria, M.; Werber, G. J.
Heterocycl. Chem. 1996, 33, 863–872; (b) Noto, R.;
Buccheri, F.; Cusmano, G.; Gruttadauria, M.; Werber,
G. J. Heterocycl. Chem. 1991, 28, 1421–1427.

F. Vergne et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4607–4613
4613
12. (a) Dahle, N. A. U.S. Patent 4,020,078, 1977; (b) Kirk-
patrick, J. L.; Rutter, J. L. DE 3025559, 1981; (c) Lender,
A.; Dollinger, M.; Santel, H. J. DE 4418066 A1, 1995.
13. All the compounds illustrated in this report were not
selective for either enzyme subtype PDE7Aor PDE7B. Con-
sequently, only PDE7Ainhibitory activities are presented.