3098
M. P. DeNinno et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3095–3098
250
100
75
50
Figure 7. Structure of 30 used as the ligand in homology model docking
experiments.
25
This conformation, in which the amide group was in an axial
configuration, would be readily accessible in compound 2 given
the lack of any A1-3 strain. It would also explain the preference
for the trans isomer in the nipecotic analogs, since the cis isomers
would force both substituents in a di-axial arrangement. The abso-
lute configuration of the amide was also the same as the single
enantiomer nipecotic amide analogs 27 and 28 further supporting
this binding model.
10
5
Colored by diastereomer
cis trans NA
0.5
1
1.5
2
2.5
3
3.5
4
cLogD
In summary, the first highly potent and selective PDE8 inhibi-
tors have been identified. A scaffold-hopping exercise was success-
fully utilized to circumvent a reactive metabolite issue. Efforts to
reduce microsomal turnover through lowering lipophilicity led
to an interesting observation that the cis diastereomers were
significantly more stable in human microsomes than the trans.
Although the microsomal clearance of the series was responsive
to reductions in lipophilicity, it could not be moved into a range
deemed sufficiently low for clinical study. The disclosure and
optimization of additional PDE8B scaffolds will be the subject of
future publications.
Figure 5. Correlation of microsomal stability versus c log D. Pairs of diastereomers
are connected with dotted lines.
Table 4
Data for individual isomers of 24
N
O
N
O
O
O
N
O
N
H
Supplementary data
Isomer
PDE8B IC50
43 nM
HLM Clint
pKa
log D
Supplementary data associated with this article can be found, in
trans 1
trans 2
cis 1
48
49
<8
<8
7.2
1.0
1.0
0.8
0.8
>10
>10
>10
l
l
l
M
M
M
7.8
cis 2
References and notes
1. Hayashi, M.; Matsushima, K.; Ohashi, H.; Tsunoda, H.; Murase, S.; Kawarada, Y.;
Tanaka, T. Biochem. Biophys. Res. Commun. 1998, 250, 751.
2. Soderling, S. H.; Bayuga, S. J.; Beavo, J. A. Proc. Natl. Acad. Sci. U.S.A. 1998, 95,
8991.
3. Soderling, S. H.; Bayuga, S. J.; Beavo, J. A. J. Biol. Chem. 1998, 273, 15553.
4. Dov, A.; Abramovitch, E.; Warwar, N.; Nesher, R. Endocrinology 2008, 149, 741.
5. Horvath, A.; Giatzakis, C.; Tsang, K.; Greene, E.; Osorio, P.; Boikos, S.; Libè, R.;
Patronas, Y.; Robinson-White, A.; Remmers, E.; Bertherat, J.; Nesterova, M.;
Stratakis, C. A. Eur. J. Genet. 2008, 16, 1245.
6. Pyne, N. J.; Furman, B. L. Diabetologia 2003, 46, 1179.
7. Pratley, R. E.; Gilbert, M. Rev. Diabet. Stud. 2008, 5, 73.
8. Such isoform selectivity has been a major issue in past PDE research, due to a
highly conserved catalytic domain among PDE family; see: Ke, H.; Wang, H.
Curr. Top. Med. Chem. 2007, 7, 391.
9. Selectivity was >1000-fold for all other PDE isoforms except PDE8A
(IC50 = 1.8 nM).
10. The isoquinoloinium species 3 was identified upon incubation with human
liver microsomes, and was shown to alkylate glutathione in this assay. See
Mutlib, A. E.; Shockcor, J. P. (2003) In Drug Metabolizing Enzymes-Cytochrome
P450 and Other Enzymes in Drug Discovery and Development Lee, J.S.; Obach, R.
S.; Fisher, M.B., Eds.; Fontis Media, S.A., Lausanne, Switzerland, p 33.
11. Unless otherwise noted and where applicable, compounds were tested as
diastereomerically pure racemic mixtures. Analogs containing an
enantiomerically pure amide substituent (e.g., 24) were mixtures of
diastereomers.
Figure 6. Homology model of 30 binding to PDE8B catalytic domain.
12. Rat PK for compound 12: Cl = 98 ml/min/kg; Vdss = 1.4 L/kg; F = 7%; rat PK for
compound 24: Cl = 146 ml/min/kg; Vdss = 2.1 L/kg.
13. van de Waterbeemd, H.; Smith, D. A.; Jones, B. C. J. Comput. Aided Mol. Des.
2001, 15, 273.
14. Data for the complete set of analogs can be found in the Supplementary data.
of Pro270. (3) A hydrogen bond from Tyr64 to the oxazole ring oxy-
gen atom, perhaps through a water molecule.