Quinazolines as potent and highly selective PDE5 inhibitors as potential therapeutics for male erectile dysfunction

Article abstract of DOI:10.1016/j.bmcl.2008.09.108

In an effort to minimize side effects associated with low selectivity against PDE isozymes, we have successfully identified a series of 6,7,8-substituted quinzaolines as potent inhibitors of PDE5 with high level of isozyme selectivity, especially against PDE6 and PDE11. PDE5 potency and isozyme selectivity of quinazolines were greatly improved with substitutions both at 6- and 8-position. The synthesis, structure-activity relationships and in vivo efficacy of this novel series of potent PDE5 inhibitors are described.

Full text of DOI:10.1016/j.bmcl.2008.09.108

Bioorganic & Medicinal Chemistry Letters 18 (2008) 6279–6282
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Quinazolines as potent and highly selective PDE5 inhibitors as potential
therapeutics for male erectile dysfunction
Young Hoon Kim a,d, Hojin Choi a, Jaekwang Lee a, In-Chang Hwang a, Seung Kee Moon a, Soo Jin Kim a,
Hong Woo Lee a, Dai Sig Im a, Sung Sook Lee a, Soon Kil Ahn a, Sang Woong Kim b, Cheol Kyu Han c,
a,
Jeong Hyeok Yoon c, Kyung Joo Lee a, , Nam Song Choi
*
*
a Chong Kun Dang Research Institute, CKD Pharmaceuticals Inc., PO Box 74, Chonan, Republic of Korea
b LeadGenex, Venture Town Dasan, 1687-2 Shinil-dong, Daedeok-gu, Daejeon, Republic of Korea
c Equispharm Inc., Gyeonggi Bio-center, Suwon, Gyeonggi-do 443-766, Republic of Korea
d Department of Chemistry, Soong Sil University, Seoul 156-743, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
In an effort to minimize side effects associated with low selectivity against PDE isozymes, we have suc-
cessfully identified a series of 6,7,8-substituted quinzaolines as potent inhibitors of PDE5 with high level
of isozyme selectivity, especially against PDE6 and PDE11. PDE5 potency and isozyme selectivity of quin-
azolines were greatly improved with substitutions both at 6- and 8-position. The synthesis, structure–
activity relationships and in vivo efficacy of this novel series of potent PDE5 inhibitors are described.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 24 June 2008
Revised 13 August 2008
Accepted 20 September 2008
Available online 11 October 2008
Keywords:
PDE5
PDE6
PDE11
Inhibitor
Quinazoline
MED
Male erectile dysfunction (MED) was a largely unmet medical
need before the introduction of sildenafil (ViagraÒ) in 1998. As a
potent inhibitors of phosphodiesterase 5 (PDE5) in the corpus cav-
ernosum of the penis, it was originally studied for the treatment of
angina before its effectiveness in treating MED was found in clini-
cal trials serendipitously.1 Increased levels of cGMP leads to de-
creased intracellular calcium in the cells of corpus cavernosum,
resulting in vasorelaxation, inflow of arterial blood, and ultimately
an erection.2 As PDE5 is a member of phosphodiesterase family of
enzymes metabolizing cGMP in penis, inhibition of PDE5 increases
the cGMP concentration, enhancing the erection.3
turbances associated with use of PDE5 inhibitors can be linked to
inhibition of PDE6, which controls function of rod and cone cells
within the eye.5 The function of PDE11 remains largely unknown,
The launch of ViagraÒ and vardenafil (LevitraÒ)4 marked the
new age in drug discovery by affecting one’s quality-of-life, how-
ever, despite their success, side effects such as headache, nausea,
flushing, and visual disturbances have been noted, which are asso-
ciated with low selectivity against other PDE isozymes, most nota-
bly PDE1 and PDE6.5 Although tadalafil (CialisÒ) was shown to
have a better PDE1 and PDE6 selectivity, it is not free from side ef-
fects such as headache, indigestion, and back pain.6 The visual dis-
* Corresponding authors. Tel.: +82 41 529 3324; fax: +82 41 558 3004 (K.J.L.); tel.:
+82 41 529 3320; fax: +82 41 558 3004 (N.S.C.).
E-mail addresses: kjlee@ckdpharm.com (K.J. Lee), nschoi@ckdpharm.com (N.S.
Choi).
Figure 1. Some representative heterocyclic PDE5 inhibitors.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.09.108

6280
Y. H. Kim et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6279–6282
Table 1
In this communication, we disclose the discovery of novel,
PDE5 activity of quinazoline derivatives
6,7,8-substituted quinazoline-based PDE5 inhibitors which exhibit
good potency and high levels of selectivity over other PDE isoforms
especially PDE6 and PDE11 as well as potent in vivo efficacy in
inducing penile erection in conscious rabbit model.
Screening of focused in-house library yielded a 4-(3-chloro-4-
methoxy)benzylamino substituted quinazoline hit (6) for PDE5,
which is equipotent to tadalafil (Table 1). Initially, there was a con-
cern about this quinazoline scaffold because of its prevalence in
protein kinase inhibitors, most of which showed potent anticancer
activity.12 However, it was found that 4-aniline or 4-phenol substi-
tution is required to possess anticancer activity, whereas our PDE5
inhibitors contain 4-benzylamino group, which is devoid of cyto-
toxicity. Quinazoline with simple substitution at 6-, 7-, or 8-posi-
tion was described13 as potent inhibitors of several PDEs’, but no
selectivity data against PDE6 and PDE11 had been reported
let alone the in vivo efficacy for erectile dysfunction.
The quinazolines in this study were obtained in a straightfor-
ward manner and their synthesis is shown in Scheme 1. The C-4
carbonyl group of 4 or 513 was chlorinated (SOCl2), followed by
reaction with 3-chloro-4-methoxybenzyl amine to give 6 or 7 in
good yield. With appropriate amines or sodium methoxide, com-
pound 6 (or 7) was converted to 8, 9 and 10 (see Table 1 for sub-
stitution pattern), while reaction with allyl alcohol gave
intermediate 11. Allyl group was incorporated at C8 by Claisen
rearrangement (xylene, 150 °C in sealed tube) of 12 and C7 hydro-
xyl group was capped with methyl to give 13 for further modifica-
tion. Selective reduction of C6 (SnCl2, EtOH) afforded 14, which
was used for further allyl group modification (vide infra).
Compound
R6
R7
Cl
R8
H
PDE5a
0.008
6
No2
8
9
No2
No2
H
0.57
H
H
0.071
10
12
13
14
No2
No2
No2
NH2
OMe
OH
0.032
0.012
0.012
1.1
OMe
OMe
Tadalafil
Sildenafil
0.012
0.01
a
IC50 values are reported in lM (values are mean of >2 determinations).
but potential role in male reproduction was recently suggested
from several lines of evidences.7 Since tadalafil cross reacts with
PDE11 at sub
selectivity. Therefore, the identification of highly selective, espe-
cially against PDE1, PDE6 and PDE11 as well as more potent
PDE5 inhibitors is of great medicinal and commercial interest.
Thus, there have been numerous efforts toward the discovery of
more isozyme selective PDE5 inhibitors8 and some representative
examples (19, 210, and 311) are shown in Figure 1.
The effect of modification with simple R6, R7, and R8 is shown
in Table 1. Tadalafil was used as a positive reference together with
sildenafil.14 By varying the amine substituent at C4 of the quinaz-
oline, we identified 3-chloro-4-methoxybenzylamine as the opti-
mal amine for PDE5 inhibitory potency, which was also observed
in several heterocyclic PDE5 inhibitors.15 Introduction of longer
ethylenediamine group (8) at C7 resulted in a dramatic loss of
activity, while shorter dimethylamino linker (9) was also detri-
lM range, there is a growing concern over PDE11
Scheme 1. Reagents and conditions: (a) 1—DMF (cat), SOCl2, 2—3-chloro-4-methoxybenzylamine, Et3N, isopropyl alcohol; (b) amine, DIPEA, DMF or NaOMe, MeOH or allyl
alcohol, NaH, DMF; (c) xylene, 150 °C, sealed tube; (d) CH3I, K2CO3, acetone, reflux; (e) SnCl2, EtOH, reflux; (f) 1—H2, PtO2, MeOH; 2—amide formation; (g) 1—amide formation,
2—OsO4/NaIO4, then reductive amination (NaCNBH3, AcOH) or NaBH4, MeOH, 0 °C.

Y. H. Kim et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6279–6282
6281
Table 2
and moreover overall property required to be efficacious in animal
model could be controlled by slight modification of this alkyl
chains, which proved to be so.
PDE5 activity and isozyme selectivity of 4-(3-chloro-4-methoxy)-benzylamino-7-
methoxy quinazoline derivatives
Compound 12 and methoxy analog (13) showed better activity
than des-allyl analog (10) by 3-fold, supporting our rationale. C7
hydroxyl analog (12) was equipotent to methoxy analog, however,
due to a concern of metabolic instability, we decided to cap free
hydroxyl group by methylation and most of derivatives maintain
methoxy at C7 position. Interestingly, the activity was abolished
in the case of 14 in which C6 nitro group was reduced to give ani-
line. Although it was not clear why the activity dropped sharply,
we envisioned that this amino group in 14 would serve as another
handle for further modification and the chemistry to provide ana-
logs with C8 variation is shown in Scheme 1. The nitro and allyl
group in 13 were reduced simultaneously (H2/PtO2), followed by
amide formation to provide 15–20 with n-propyl group at C8. Con-
versely, starting from 14 various amide groups were first intro-
duced at C6 position with suitable acid or anhydride, followed by
OsO4/NaIO4 oxidation to give aldehyde intermediates, from which
21 and 22 were obtained by reductive amination or 25–2816 were
obtained by reduction (NaBH4/MeOH). Simple amide formation of
14 without changing C8 position gave compounds 23 and 24.
Then, we probed the effect of substitution both at C6 and C8 po-
sition, with selectivity profiling against PDE6 and PDE11. Since
many derivatives can be prepared rapidly by amide formation
reaction of C6 amine with a range of alkyl- and aryl-acetic acids,
we initially synthesized focused library with C6 amide linkage.
This effort afforded many potent and selective PDE5 inhibitors as
indicated in Table 2. We were delighted to observe that trifluoro-
acetamido derivative 15 significantly improved PDE5 activity by
about 300-fold compared to 14 with excellent selectivity against
PDE6 and PDE11. As mentioned before, many side effects of cur-
rently marketed drugs especially visual disturbances are ascribed
to PDE6 inhibition because PDE6 is the sole cGMP PDE in the retina.
In addition, tadalafil, a more selective against PDE6 than sildenafil,
suffered from poor PDE11 selectivity as described earlier.6 In an ef-
fort to discover novel, potent PDE5 inhibitors with excellent PDE6
and PDE11 selectivity, most of derivatives were routinely screened
against these isozymes.
Compound
R
R8
PDE5a
0.004
PDE6a
0.44
PDE11a
7.1
15
CF3
16
17
18
19
20
H2NCH2-
CH3
0.029
0.018
0.019
0.005
0.014
ND
ND
4.5
22.7
14.7
7.7
c-Propyl
Ethyl
0.82
0.42
3.7
tert-Butyl
9.5
21
22
CF3
CF3
0.019
0.014
14.1
ND
39.3
ND
23
24
25
26
27
28
Ethyl
0.018
0.032
0.01
0.79
ND
7.8
ND
n-Propyl
CH3
5.9
24.3
ND
2-Pyridyl
i-Propyl
Ethyl
1.6
ND
0.021
0.001
2.4
7.7
0.46
10.5
Tadalafil
Sildenafil
0.012
0.01
18.1
0.14
0.29
3.0
Changing trifluoromethyl group to various alkyl groups showed
clear SAR that PDE5 activity of analogs 16, 17, 18, and 20 (R = ami-
nomethyl, Me, cyclopropyl, and tert-butyl, respectively) were very
similar and slightly lower than tadalafil while isozyme selectivity
remains good in all cases (Table 2). The inhibitory activity was im-
proved with ethyl analog (19) and the ethyl appears to be optimal
within this small set of series. This trend was also observed in the
case of C8 allyl analogs (23 vs 24) although the PDE5 potency was
slightly inferior to C8 n-propyl analogs (19 vs 23). The effect of lar-
ger polar functionality at C8 was explored in 21 and 22, and there
a
Enzyme sources: see Ref. 18. IC50 values are reported in
lM (values are mean of
>2 determinations). ND, not determined.
mental. No other bulky functional groups gave better activity than
simple methoxy group (data not shown), and for reasons of syn-
thetic convenience and molecular weight increase, we decided to
maintain methoxy group at C7 position. Regarding C8 position,
we assumed that small alkyl groups would impart better activity
Figure 2. Effects of 25 (a), and 28 (b) on the length of penis in conscious rabbit model. The length of penis was measured after oral administration of 25 and 28, followed by a
sodium nitroprusside (SNP, 0.1 mg/kg) injection after 60 min (n = 4). See Ref. 17 for details.

6282
Y. H. Kim et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6279–6282
was a slight loss of PDE5 activity when compared with 15,
although the selectivity has been increased.
lacks in vivo efficacy in conscious rabbit model when dosed orally,
which was ascribed to low membrane permeability. When polar
hydroxyethyl group was incorporated at C8 (25 and 28), physico-
chemical properties such as Caco-2 permeability and protein bind-
ing were substantially improved. Compound 28 is not only more
potent (10-fold) than tadalafil and sildenafil for PDE5, but highly
selective against many PDE isozymes (selectivity ratios for
PDE6 > 470, PDE11 > 8600, PDE1 > 2000, PDE2 > 8600, and
PDE3 > 20,000). Moreover, both 25 and 28, were orally effective
in conscious rabbit model, demonstrating equal efficacy compared
to tadalafil. Thus, because of its improved PDE isozyme selectivity
profile compared with sildenafil and tadalafil, compounds 25 and
28 might be expected have fewer side effects if used for the treat-
ment of MED.
In order to evaluate the oral efficacy of a compound in induc-
ing the penile erection, conscious rabbits were used in this
study.17 Initially, 15 was evaluated in this model, but despite
excellent PDE5 potency, 15 was shown to be far less efficacious
than tadalafil (data not shown), and we hypothesized that low
membrane permeability and/or high protein binding (>99%) was
attributed to low efficacy. Therefore, we turned our attention to
the preparation of derivatives that have high membrane perme-
ability as well as relatively lower protein binding, and we believe
this could be achieved by introduction of polar functional groups
instead of simple alkyl groups at C8 position. As depicted in
Scheme 1, oxidation with OsO4/NaIO4 followed by reduction gave
C8 hydroxyethyl analogs (Table 2). Other analogs including car-
boxylic acid, amino, and 1,2-diol functionality were also prepared
and screened as PDE5 inhibitors; however, C8 hydroxyethyl ana-
logs were consistently the best moiety in terms of activity and
synthetic convenience as well as PDE5 potency. Gratifyingly, acet-
amido analog with C8 hydroxyethyl group (25) improved PDE5
activity by 2-fold relative to 17, while isozyme selectivity remains
the same. Incorporation of aromatic group in 26 resulted in dra-
matic loss of activity suggesting that there might be an optimal
steric requirement at C8 position. With isopropyl group in 27 re-
stored activity, although it is 2-fold inferior to methyl analog 25.
Of special note is the propionamide analog 28 which was 10-fold
more potent than sildenafil and tadalafil and represent the most
potent in our series. Compound 28 is not only 10-fold more po-
tent than tadalafil and sildenafil, it is significantly selective
against other PDE isozymes as indicated in Table 2 (selectivity
for PDE6 > 470 and PDE11 > 8700) and this ratios were also found
References and notes
1. (a) Martel, A. M.; Graul, A.; Rabasseda, X.; Castaner, R. Drugs Future 1997, 22,
138; (b) Terret, N. K.; Bell, A. S.; Brown, D.; Ellis, P. Bioorg. Med. Chem. Lett. 1996,
6, 1819.
2. (a) Gibson, A. Eur. J. Pharmacol. 2001, 411, 1; (b) Andersson, K.-E.; Wagner, G.
Physiol. Rev. 1995, 75, 191.
3. (a) Rotella, D. P. Nat. Rev. Drug Discov. 2002, 1, 674; (b) Manallack, D. T.;
Hughes, R. A.; Thompson, P. E. J. Med. Chem. 2005, 48, 3449.
4. (a) Osterloh, I. H.; Riley, A. Br. J. Clin. Pharmacol. 2002, 53, 219; (b) Beavo, J. A.
Physiol. Rev. 1995, 75, 725.
5. Bischoff, E. Int. J. Impot. Res. 2004, 16, S34.
6. (a) Daugan, A.; Grondin, P.; Ruault, C.; Coste, H.; Kirilovsky, J.; Hyafil, F. J. Med.
Chem. 2003, 46, 4525; (b) Porst, H. EAU Update Ser. 2004, 2, 56.
7. (a) Makhlouf, A.; Kshirsagar, A.; Niederberger, C. Int. J. Impot. Res. 2006, 18, 501;
(b) Francis, S. H. Int. J. Impot. Res. 2005, 17, 467; (c) Seftel, A. D. J. Urol. 2005, 174,
1043.
8. (a) Giovannoni, M. P.; Vergelli, C.; Biancalani, C.; Cesari, N.; Graziano, A.;
Biagini, P.; Gracia, J.; Gavalda, A.; Dal Piaz, V. J. Med. Chem. 2006, 49, 5363; (b)
Jiang, W.; Guan, J.; Macielag, M. J.; Zhang, S.; Kraft, Y.; John, T. M.; H.-J., D.;
Lunden, S.; Sui, Z. J. Med. Chem. 2005, 48, 2126; (c) Haning, H.; Niewoehner, U.;
Schenke, T.; Lampe, T.; Hillish, A.; Bischoff, E. Bioorg. Med. Chem. Lett. 2005, 15,
3900; (d) Xia, G.; Li, J.; Peng, A.; Lai, S.; Zhang, S.; Shen, J.; Liu, Z.; Chen, X.; Ji, R.
Bioorg. Med. Chem. Lett. 2005, 15, 2790.
9. Bi, Yingzhi; Stoy, P.; Ada, L.; He, B.; Krupinski, J.; Normandin, D.; Pongrac, R.;
Seliger, L.; Watson, A.; Macor, J. Bioorg. Med. Chem. Lett. 2004, 14, 1577.
10. Watanabe, N.; Kabasawa, Y.; Takase, Y.; Matsukura, M.; Miyazaki, K.; Ishihara,
H.; Kodama, K.; Adachi, H. J. Med. Chem. 1998, 41, 3367.
11. Arnold, N. J.; Beer, D.; Bhalay, G.; Craig, S.; Farr, D.; Glen, A.; Hatto, J. D.; Jones,
D.; Moser, H. E.; Naef, R.; Turner, K. L.; Tweed, M. F.; Watson, S. J.; Zurini, M.
Bioorg. Med. Chem. Lett. 2007, 17, 2376.
12. (a) Vieth, M.; Sutherland, J. J.; Robertson, D. H.; Campbell, R. M. Drug Discov.
Today 2005, 10, 839; (b) Scapin, G. Drug Discov. Today 2002, 7, 601.
13. Takase, Y.; Saeki, T.; Watanabe, N.; Adachi, H.; Souda, S.; Saito, I. J. Med. Chem.
1994, 37, 2106.
14. PDE5 assays were carried out as described in: Turko, I. V.; Ballard, S. A.; Francis,
S. H.; Corbin, J. D. Mol. Pharm. 1999, 56, 124. Assays for other isozymes were
conducted in a similar manner..
15. (a) Rotella, D. P.; Sun, Z.; Zhu, Y.; Krupinski, J.; Pongrac, R.; Sliger, L.;
Normandin, D.; Macor, J. E. J. Med. Chem. 2000, 43, 5037; (b) Bi, Y.; Stoy, P.;
Adam, L.; He, B.; Krupinski, J.; Mormandin, D.; Pongrac, R.; Seliger, L.; Watson,
A.; Macor, J. E. Bioorg. Med. Chem. Lett. 2001, 11, 2461.
to be very large against PDE1, PDE2, and PDE3 (IC50 = 2.4
lM,
10.4 M, and 25.5
l
l
M, respectively).18
As mentioned before, we expected that incorporation of polar
functionality would lead to compounds that possess more prefera-
ble physicochemical properties such as solubility, membrane per-
meability, and protein binding. With highly potent derivatives in
our hands, selected compounds (25 and 28) were further assessed
for animal study. In contrast to 15 which has very low permeability
and high protein binding, both 25 and 28 were found to have excel-
lent Caco-2 permeability19 (17.3 Â 10À6 cm sÀ1 and 46.9 Â 10À6
cm sÀ1, respectively) and moderate protein binding relative to sil-
denafil (95% each, and 98% for sildenafil). Metabolic stability issue
was excluded since both 15 and 28 had fairly good microsomal sta-
bilities (>80% of parent compounds were remained after incuba-
tion for 1 h in rat and rabbit liver microsomes).
Encouraged by these results, both compounds (as hydrochloride
salts) were evaluated in conscious rabbit model as described ear-
lier17 (Fig. 2). Both compounds demonstrated equal efficacy com-
pared to tadalafil (3 mg/kg) when dosed orally and this effect
was shown to be dose-dependent (3 and 10 mg/kg) for both 25
and 28. No penile erection was observed in vehicle-treated ani-
mals, while the erectogenic effect was potentiated by SNP injection
(0.1 mg/kg), a nitric oxide donor that was used as a sexual stimu-
lant. When dosed alone at 3 mg/kg, negligible erection was ob-
served in both analogs; however, a significant penile erection
was potentiated at 10 mg/kg even in the absence of SNP injection.
It is interesting to note that Caco-2 permeability and protein bind-
ing were major predictors for oral in vivo efficacy of our quinazo-
line series as clearly demonstrated by 15 vs 25 and 28.
16. Selected data for 15: 1H NMR (400 MHz, DMSO-d6) d 8.53 (s, 1H), 8.47 (s, 1H),
8.17 (m, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.37 (dd, J = 8.5, 2.1 Hz, 1H), 7.05 (d,
J = 8.5 Hz, 1H), 4.83 (m, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 3.10 (m, 2H), 1.68 (m,
2H), 0.98 (t, J = 3.8 Hz, 3H); MS (ESI) m/z 483 (M+H). For 25: 1H NMR (400 MHz,
CD3OD) d 8.51 (s, 1H), 8.43 (s, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.10 (dd, J = 8.5,
2.1 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 4.75 (s, 2H), 3.88–3.82 (m, 8H), 3.36 (m,
2H), 2.27 (s, 3H); MS (ESI) m/z 431 (M + H). For 28: 1H NMR (400 MHz, CD3OD)
d 8.50 (s, 1H), 8.41 (s, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.5, 2.0 Hz, 1H),
6.98 (d, J = 8.5 Hz, 1H), 4.73 (s, 2H), 3.89–3.81 (m, 8H), 3.35 (t, J = 6.9 Hz, 2H),
2.54 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H); MS (ESI) m/z 445 (M+H).
17. (a) Bischoff, E.; Niewoehner, U.; Haning, H.; Es Sayed, M.; Schenke, T.;
Schlemmer, K. H. J. Urol. 2001, 165, 1315; b Kang, K. K.; Ahn, G. J.; Ahn, B. O.;
Yoo, M.; Kim, W. B. Eur. Urol. 2003, 43, 689. In brief, New Zealand white rabbits
weighing 3–4 kg (n = 4) were orally dosed (dissolved in distilled water) with
compounds, followed by injection of SNP (0.1 mg/0.1 ml/kg, dissolved in
saline) after 60 min, and the length of penis (covered + mucosa area) was
measured with sliding calipers, recorded in cm for total 2 or 2.5 h after
administration of test compounds.
In summary, starting from screening hit, we have identified a
series of potent PDE5 inhibitors based on 4-benzylaminoquinazo-
line scaffold. By systematic variation of C6, C7, and C8 positions
of quinazoline scaffold through unique and efficient chemistry,
we were able to obtain potent and highly selective analogs against
PDE6 and PDE11. Initial lead compound (15), albeit potent in vitro
18. Enzyme sources: PDE1, bovine heart; PDE2, bovine heart; PDE3, bovine
platelet; PDE5, bovine platelet; PDE6, bovine retina; and PDE11, human
recombinant.
19. Artursson, P.; Tavelin, S.. In Drug Bioavailability; Waterbeemd, H., Lennernas, H.,
Artursson, P., Eds.; Wiley-VCH, 2003; Vol. 18, pp 72–89 (Methods and
Principles in Medicinal Chemistry series).