2584
S. O. Ochiana et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2582–2584
Table 2
Compound 15, showed very weak activity (17% inhibition). The
Tadalafil analogs tested against TbrPDEB1
other compounds in Table 2 show low-to-modest potency, includ-
ing those that explored the putative P-pocket. However, compound
6, which was designed to interact with a small sub-pocket adjacent
R1
O
O
to the metal binding region displayed 72% inhibition at 10 lM.
N
Unfortunately, a reliable dose–response experiment was not possi-
ble with this analog due to poor solubility at higher concentrations.
In conclusion, the goal of these experiments was to broadly ex-
plore the structure–activity relationships of the tadalafil scaffold.
Most analogs synthesized displayed a poor inhibition profile with
the notable exception of 6. Given the fairly flat SAR and low poten-
cies observed, we confirm that the tadalafil scaffold does not hold
as strong promise for potent TbrPDEB1 inhibitors as the PDE4
chemotypes previously disclosed.7
N
N
R3
R2
R1
Compound R2
Tadalafil
R3
TbrPDEB1 (% inh)a
H
H
H
0b
O
O
4a
5a
CH3
H
6.9
11.8
Acknowledgments
Br
This work was supported by the National Institutes of Health
(R01AI082577), Boston University and Northeastern University.
We gratefully acknowledge a free academic license to the OpenEye
suite of software.
5
H
Br
11.57
O
O
6
H
1H-Pyrazol-3-yl 71.8
4b
16
CH3
H
H
H
19.7
38.8
Supplementary data
3a
3b
12
H
H
H
H
H
H
21.2
9.4b
0
Full tabulation of all inhibitors prepared and screened in the
context of this project is included in the Supplementary data, along
with spectroscopic characterization of new compounds. Screening
data from this overall TbrPDE inhibitor project will be made publi-
cally available as a public data set in the Collaborative Drug Discov-
NHCbz
N
NHAc
NH
Supplementary data associated with this article can be found, in
13
H
H
H
H
0
References and notes
O
NH
N
N
1. Stuart, K.; Brun, R.; Croft, S.; Fairlamb, A.; Gurtler, R. E.; McKerrow, J.; Reed, S.;
Tarleton, R. J. Clin. Invest. 2008, 118, 1301.
2. Brun, R.; Blum, J.; Chappuis, F.; Burri, C. Lancet 2010, 375, 148.
3. Matovu, E.; Seebeck, T.; Enyaru, J. C. K.; Kaminsky, R. Microbes Infect. 2001, 3,
763.
NH
14
6.09
4. Oberholzer, M.; Marti, G.; Baresic, M.; Kunz, S.; Hemphill, A.; Seebeck, T. FASEB
J. 2007, 21, 720.
5. Laxman, S.; Beavo, J. A. Mol. Interventions 2007, 7, 203.
6. Shakur, Y.; de, K. H. P.; Ke, H.; Kambayashi, J.; Seebeck, T. Handb. Exp.
Pharmacol. 2011, 487.
a
Inhibitor concentration 10.0
Inhibitor concentration 100.0
l
l
M.
M.
b
7. Bland, N. D.; Wang, C.; Tallman, C.; Gustafson, A. E.; Wang, Z.; Ashton, T. D.;
Ochiana, S. O.; McAllister, G.; Cotter, K.; Fang, A. P.; Gechijian, L.; Garceau, N.;
Gangurde, R.; Ortenberg, R.; Ondrechen, M. J.; Campbell, R. K.; Pollastri, M. P. J.
Med. Chem. 2011, 54, 8188.
8. Pollastri, M. P.; Campbell, R. K. Future Med. Chem. 2011, 3, 1307.
9. Wang, C.; Ashton, T. D.; Gustafson, A.; Bland, N. D.; Ochiana, S. O.; Campbell, R.
10. Seebeck, T.; Sterk, G. J.; Ke, H. Future Med. Chem. 2011, 3, 1289.
11. Beghyn, T. B.; Charton, J.; Leroux, F.; Laconde, G.; Bourin, A.; Cos, P.; Maes, L.;
Deprez, B. J. Med. Chem. 2011, 54, 3222.
12. Deprez, B.; Beghyn, T.; Laconde, G.; Charton, J., 2008, WO2008044144A2.
13. Sung, B. J.; Hwang, K. Y.; Jeon, Y. H.; Lee, J. I.; Heo, Y. S.; Kim, J. H.; Moon, J.;
Yoon, J. M.; Hyun, Y. L.; Kim, E.; Eum, S. J.; Park, S. Y.; Lee, J. O.; Lee, T. G.; Ro, S.;
Cho, J. M. Nature 2003, 425, 98.
of 3a (Scheme 4) by catalytic hydrogenation provided the amine
template 11, that could be acylated (to provide 12 or 13) or alkyl-
ated (to provide 14). These analogs were designed in order to both
probe the steric accessibility of the P-pocket, and to interact with
the putative H-bond donors/acceptors present.
Finally, 15 was prepared in an analogous manner to the analogs
shown in Scheme 1, starting from tryptamine (Scheme 5).
All the tadalafil analogs synthesized were screened against
TbrPDEB17 and the data is summarized in Tables 1 and 2. The
tricyclic analogs in Table 1 show weak activity. Although tadalafil
14. Wang, H.; Yan, Z.; Geng, J.; Kunz, S.; Seebeck, T.; Ke, H. Mol. Microbiol. 2007,
1029, 66.
showed no inhibition at 100
lM (Table 2) its C6 epimer 16
displayed almost 40% inhibition at the same concentration.